The individual immediately began wheezing, coughing with dyspnea, and
recovered without treatment within five minutes. The author believes
that the worker developed his asthma from inhaling potassium
bichromate.
    In addition to the case reports confirming that Cr(VI) is
responsible for the development of asthma using inhalation challenge
tests, there are several other case reports of Cr(VI) exposed workers
having symptoms consistent with asthma where the symptoms were never
confirmed by using inhalation challenge tests.
    Lockman reported a case of a 41-year-old woman who was
occupationally exposed to potassium dichromate during leather tanning
(Ex. 35-14). The worker developed an occupational allergy to potassium
dichromate. This allergy involved both contact dermatitis and asthma.
The physicians considered other challenge tests using potassium
dichromate as the test agent (i.e., peak expiratory flow rate, forced
expiratory volume in 1 second and methacholine or bronchodilator
challenge), but the subject changed jobs before the physicians could
administer these tests. Once the subject changed jobs, all her symptoms
disappeared. It was not confirmed whether the occupational exposure to
Cr(VI) was the cause of the asthma.
    Williams reported a 23-year-old textile worker who was
occupationally exposed to chromic acid. He worked near two tanks of
chromic acid solutions (Ex. 35-23) and inhaled fumes while frequently
walking through the room with the tanks. He developed both contact
dermatitis and asthma. He believes the tank was poorly ventilated and
was the source of the fumes. He stopped working at the textile firm on
the advice of his physician. After leaving, his symptoms improved
greatly. No inhalation bronchial challenge testing was conducted to
confirm that chromic acid was causing his asthmatic attacks. However,
as noted above, chromic acid exposure has been shown to lead to
occupational asthma, and thus, chromic acid was likely to be a
causative agent in the development of asthma.
    Park et al. reported a case of four workers who worked in various
occupations involving exposure to either chromium sulfate or potassium
dichromate (Ex. 35-18). Two worked in a metal electroplating factory,
one worked at a cement manufacturer, and the other worked in
construction. All four developed asthma. One individual had a positive
response to a bronchial provocation test (with chromium sulfate as the
test agent). This individual developed an immediate reaction,
consisting of wheezing, coughing and dyspnea, upon being given chromium
sulfate as the test agent. Peak expiratory flow rate decreased by about
20%. His physician determined that exposure to chromium sulfate was
contributing to his asthma condition. Two other individuals had
positive reactions to prick skin tests with chromium sulfate as the
test agent. Two had positive responses to patch tests using potassium
dichromate as the testing challenge agent. Only one out of four
underwent inhalation bronchial challenge testing (with a positive
result to chromium sulfate) in this report.
3. Bronchitis
    In addition to nasal ulcerations, nasal septum perforations, and
asthma, there is also limited evidence from reports in the literature
of bronchitis associated with Cr(VI) exposure. It is not clear what
occupational exposure levels of Cr(VI) compounds would lead to the
development of bronchitis.
    Royle found that 28% (104/288) of British electroplaters developed
bronchitis upon inhalation exposure to chromic acid, as compared to 23%
(90/299) controls (Ex. 7-50). The workers were considered to have
bronchitis if they had symptoms of persistent coughing and phlegm
production. In all but two cases of bronchitis, air samples revealed
chromic acid at levels of 0.03 mg/m\3\. Workers were asked to fill out
questionnaires to assess respiratory problems. Self-reporting poses a
problem in that the symptoms and respiratory health problems identified
were not medically confirmed by physicians. Workers in this study
believe they were developing bronchitis, but it is not clear from this
study whether the development of bronchitis was confirmed by
physicians. It is also difficult to assess the bronchitis health
effects of chromic acid from this study because the study results for
the exposed (28%) and control groups (23%) were similar.
    Alderson et al. reported 39 deaths of chromate production workers
related to chronic bronchitis from three chromate producing factories
(Bolton, Eaglescliffe, and Rutherglen) from 1947 to 1977 (Ex. 35-2).
Neither the specific Cr(VI) compound nor the extent or frequency with
which the workers were exposed were specified. However, workers at all
three factories were exposed to sodium chromate, chromic acid, and
calcium chromate at one time or another. The authors did not find an
excess number of bronchitis related deaths at the Bolton and
Eaglescliffe factories. At Rutherglen, there was an excess number of
deaths (31) from chronic bronchitis with a ratio of observed/expected
of 1.8 (p< 0.001). It is difficult to assess the respiratory health
effects of Cr(VI) compounds from this study because there are no
exposure data, there are no data on smoking habits, nor is it clear the
extent, duration, and amount of specific Cr(VI) compound to which the
workers were exposed during the study.
    While the evidence supports an association between bronchitis and
Cr(VI) exposure is limited, studies in experimental animals demonstrate
that Cr(VI) compounds can cause lung irritation, inflammation in the
lungs, and possibly lung fibrosis at various exposure levels. Glaser et
al. examined the effects of inhalation exposure of chromium (VI) on
lung inflammation and alveolar macrophage function in rats (Ex. 31-18-
9). Twenty, 5-week-old male TNO-W-74 Wistar rats were exposed via
inhalation to 25-200 [mu]g Cr(VI)/m3 as sodium dichromate
for 28 days or 90 days for 22 hours per day, 7 days per week in
inhalation chambers. Twenty, 5-week-old male TNO-W-74 Wistar rats also
served as controls. All rats were killed at the end of the inhalation
exposure period. The authors found increased lung weight in the 50-200
[mu]g/m3 groups after the 90-day exposure period. They also
found that 28-day exposure to levels of 25 and 50 [mu]g/m3
resulted in ``activated'' alveolar macrophages with stimulated
phagocytic activities. A more pronounced effect on the activation of

alveolar macrophages was seen during the 90-day exposure period of 25
and 50 [mu]g/m3.
    Glaser et al. exposed 150 male, 8-week-old Wistar rats (10 rats per
group) continuously by inhalation to aerosols of sodium dichromate at
concentrations of 50, 100, 200, and 400 [mu]g Cr(VI)/m3 for
22 hours per day, 7 days a week, for continuous exposure for 30 days or
90 days in inhalation chambers (Ex. 31-18-11). Increased lung weight
changes were noticeable even at levels as low as 50 and 100 [mu]g
Cr(VI)/m3 following both 30 day and 90 day exposures.
Significant accumulation of alveolar macrophages in the lungs was noted
in all of the exposure groups. Lung fibrosis occurred in eight rats
exposed to 100 [mu]g Cr(VI)/m3 or above for 30 days. Most
lung fibrosis disappeared after the exposure period had ceased. At 50
[mu]g Cr(VI)/m3 or higher for 30 days, a high incidence of
hyperplasia was noted in the lung and respiratory tract. The total
protein in bronchoalveolar lavage (BAL) fluid, albumin in BAL fluid,
and lactate dehydrogenase in BAL fluid were significant at elevated
levels of 200 and 400 [mu]g Cr(VI)/m3 in both the 30 day and
90 day exposure groups (as compared to the control group). These
responses are indicative of severe injury in the lungs of animals
exposed to Cr(VI) dose levels of 200 [mu]g Cr(VI)/m3 and
above. At levels of 50 and 100 [mu]g Cr(VI)/m3, the
responses are indicative of mild inflammation in the lungs. The authors
concluded that these results suggest that the severe inflammatory
reaction may lead to more chronic and obstructive lesions in the lung.
4. Summary
    Overall, there is convincing evidence to indicate that Cr(VI)
exposed workers can develop nasal irritation, nasal ulcerations, nasal
perforations, and asthma. There is also some limited evidence that
bronchitis may occur when workers are exposed to Cr(VI) compounds at
high levels. Most of the studies involved exposure to water-soluble
Cr(VI) compounds. It is very clear that workers may develop nasal
irritations, nasal ulcerations, and nasal perforations at levels below
the current PEL of 52 [mu]g/m3. However, it is not clear
what occupational exposure levels lead to disorders like asthma and
bronchitis.
    There are numerous studies in the literature showing nasal
irritations, nasal perforations, and nasal ulcerations resulting from
Cr(VI) inhalation exposure. It also appears that direct hand-to-nose
contact (i.e., by touching inner nasal surfaces with contaminated
fingers) can contribute to the incidence of nasal damage. Additionally,
some studies show that workers developed these nasal health problems
because they did not wear any PPE, including respiratory protection.
Inadequate area ventilation and sanitation conditions (lack of
cleaning, dusty environment) probably contributed to the adverse nasal
effects.
    There are several well documented case reports in the literature
describing occupational asthma specifically triggered by Cr(VI) in
sensitized workers. All involved workers who frequently suffered
symptoms typical of asthma (e.g. dyspnea, wheezing, coughing, etc.)
while working in jobs involving airborne exposure to Cr(VI). In some of
the reports, a physician diagnosed bronchial asthma triggered by Cr(VI)
after specific bronchial challenge with a Cr(VI) aerosol produced
characteristic symptoms and asthmatic airway responses. Several
national and international bodies, such as the National Institute for
Occupational Safety and Health, the World Health Organization's
International Programme on Chemical Safety, and the United Kingdom
Health and Safety Executive have recognized Cr(VI) as an airway
sensitizer that can cause occupational asthma. Despite the widespread
recognition of Cr(VI) as an airway sensitizer, OSHA is not aware of any
well controlled occupational survey or epidemiological study that has
found a significantly elevated prevalence of asthma among Cr(VI)-
exposed workers. The level of Cr(VI) in the workplace that triggers the
asthmatic condition and the number of workers at risk are not known.
    The evidence that workers breathing Cr(VI) can develop respiratory
disease that involve inflammation, such as asthma and bronchitis is
supported by experimental animal studies. The 1985 and 1990 Glaser et
al. studies show that animals experience irritation and inflammation of
the lungs following repeated exposure by inhalation to water-soluble
Cr(VI) at air concentrations near the previous PEL of 52 [mu]g/
m3.

D. Dermal Effects

    Occupational exposure to Cr(VI) is a well-established cause of
adverse health effects of the skin. The effects are the result of two
distinct processes: (1) Irritant reactions, such as skin ulcers and
irritant contact dermatitis, and (2) delayed hypersensitivity
(allergic) reactions. Some evidence also indicates that exposure to
Cr(VI) compounds may cause conjunctivitis.
    The mildest skin reactions consist of erythema (redness), edema
(swelling), papules (raised spots), vesicles (liquid spots), and
scaling (Ex. 35-313, p. 295). The lesions are typically found on
exposed areas of the skin, usually the hands and forearms (Exs. 9-9; 9-
25). These features are common to both irritant and allergic contact
dermatitis, and it is generally not possible to determine the etiology
of the condition based on histopathologic findings (Ex. 35-314).
Allergic contact dermatitis can be diagnosed by other methods, such as
patch testing (Ex. 35-321, p. 226). Patch testing involves the
application of a suspected allergen to the skin, diluted in petrolatum
or some other vehicle. The patch is removed after 48 hours and the skin
examined at the site of application to determine if a reaction has
occurred.
    Cr(VI) compounds can also have a corrosive, necrotizing effect on
living tissue, forming ulcers, or ``chrome holes'' (Ex. 35-315). This
effect is apparently due to the oxidizing properties of Cr(VI)
compounds (Ex. 35-318, p. 623). Like dermatitis, chrome ulcers
generally occur on exposed areas of the body, chiefly on the hands and
forearms (Ex. 35-316). The lesions are initially painless, and are
often ignored until the surface ulcerates with a crust which, if
removed, leaves a crater two to five millimeters in diameter with a
thickened, hardened border. The ulcers can penetrate deeply into tissue
and become painful. Chrome ulcers may penetrate joints and cartilage
(Ex. 35-317, p. 138). The lesions usually heal in several weeks if
exposure to Cr(VI) ceases, leaving a flat, atrophic scar (Ex. 35-318,
p.623). If exposure continues, chrome ulcers may persist for months
(Ex. 7-3).
    It is generally believed that chrome ulcers do not occur on intact
skin (Exs. 35-317, p. 138; 35-315; 35-25). Rather, they develop readily
at the site of small cuts, abrasions, insect bites, or other injuries
(Exs. 35-315; 35-318, p. 138). In experimental work on guinea pigs,
Samitz and Epstein found that lesions were never produced on undamaged
skin (Ex. 35-315). The degree of trauma, as well as the frequency and
concentration of Cr(VI) application, was found to influence the
severity of chrome ulcers.
    The development of chrome ulcers does not appear to be related to
the sensitizing properties of Cr(VI). Edmundson provided patch tests to
determine sensitivity to Cr(VI) in 56 workers who exhibited either
chrome ulcers or scars (Ex. 9-23). A positive response to the patch
test was found in only two of the workers examined.
    Parkhurst first identified Cr(VI) as a cause of allergic contact
dermatitis in 1925 (Ex. 9-55). Cr(VI) has since been

confirmed as a potent allergen. Kligman (1966) used a maximization test
(a skin test for screening possible contact allergens) to assess the
skin sensitizing potential of Cr(VI) compounds (Ex. 35-327). Each of
the 23 subjects was sensitized to potassium dichromate. On a scale of
one to five, with five being the most potent allergen, Cr(VI) was
graded as five (i.e., an extreme sensitizer). This finding was
supported by a guinea pig maximization test, which assigned a grade of
four to potassium chromate using the same scale (Ex. 35-328).
1. Prevalence of Dermal Effects
    Adverse skin effects from Cr(VI) exposure have been known since at
least 1827, when Cumin described ulcers in two dyers and a chromate
production worker (Ex. 35-317, p. 138). Since then, skin conditions
resulting from Cr(VI) exposure have been noted in a wide range of
occupations. Work with cement is regarded as the most common cause of
Cr(VI)-induced dermatitis (Exs. 35-313, p. 295; 35-319; 35-320). Other
types of work where Cr(VI)-related skin effects have been reported
include chromate production, chrome plating, leather tanning, welding,
motor vehicle assembly, manufacture of televisions and appliances,
servicing of railroad locomotives, aircraft production, and printing
(Exs. 31-22-12; 7-50; 9-31; 9-100; 9-63; 9-28; 9-95; 9-54; 35-329; 9-
97; 9-78; 9-9; 35-330). Some of the important studies on Cr(VI)-related
dermal effects in workers are described below.
a. Cement Dermatitis
    Many workers develop cement dermatitis, including masons, tile
setters, and cement workers (Ex. 35-318, p. 624). Cement, the basic
ingredient of concrete, may contain several possible sources of
chromium (Exs. 35-317, p.148; 9-17). Clay, gypsum, and chalk that serve
as ingredients may contain traces of chromium. Ingredients may be
crushed using chrome steel grinders that, with wear, contribute to the
chromium content of the concrete. Refractory bricks in the kiln and ash
residues from the burning of coal or oil to heat the kiln serve as
additional sources. Trivalent chromium from these sources can be
converted to Cr(VI) in the kiln (Ex. 35-317. p. 148).
    The prevalence of cement dermatitis in groups of workers with
regular contact with wet cement has been reported to be from 8 to 45
percent depending on the countries of origin, type of construction
industry, and criteria used to diagnose dermatitis (Exs. 46-74, 9-131;
35-317, 9-57, 40-10-10). Cement dermatitis can be caused by direct
irritation of the skin, by sensitization to Cr(VI), or both (Ex. 35-
317, p. 147). The reported proportion of allergic and irritant contact
dermatitis varies considerably depending on the information source. In
a review of 16 different data sets, Burrows (1983) found that, on
average, 80% of cement dermatitis cases were sensitized to Cr(VI) (Ex.
35-317, p. 148). The studies were mostly conducted prior to 1970 on
European construction workers. More recent occupational studies suggest
that Cr(VI) allergy may make up a smaller proportion of all dermatitis
in construction workers, depending on the Cr(VI) content of the cement.
For example, examination of 1238 German and Austrian construction
workers in dermatitis units found about half those with occupational
dermatitis were skin sensitized to Cr(VI) (Ex. 40-10-10). Several other
epidemiological investigations conducted in the 1980s and 1990s also
reported that allergic contact dermatitis made up 50 percent or less of
all dermatitis cases in various groups of construction workers exposed
to wet cement (Ex. 46-74).
    Cement is alkaline, abrasive, and hydroscopic (water-absorbing),
and it is likely that the irritant effect resulting from these
properties interferes with the skin's defenses, permitting penetration
and sensitization to take place more readily (Ex. 35-318, p. 624). Dry
cement is considered relatively innocuous because it is not as alkaline
as wet cement (Exs. 35-317, p. 147; 9-17). When water is mixed with
cement the water liberates calcium hydroxide, causing a rise in pH (Ex.
35-317, p. 147).
    Flyvholm et al. (1996) noted a correlation between the Cr(VI)
concentration in the local cement and the frequency of allergic contact
dermatitis (Ex. 35-326, p. 278). Because the Cr(VI) content depends
partially upon the chromium concentration in raw materials, there is a
great variability in the Cr(VI) content in cement from different
geographical regions. In locations with low Cr(VI) content, the
prevalence of Cr(VI)-induced allergic contact dermatitis was reported
to be approximately one percent, while in regions with higher chromate
concentrations the prevalence was reported to rise to between 9 to 11%
of those exposed (Ex. 35-326, p. 278). For example, only one of 35 U.S.
construction workers with confirmed cement dermatitis was reported to
have a positive Cr(VI) patch test in a 1970 NIOSH study (Ex. 9-57).
However, the same study revealed a low Cr(VI) content in 42
representative cement samples from U.S. companies (e.g 80 percent of
the samples with C(VI) <  2 [mu]g/g).
    The relationship between Cr(VI) content in cement and the
prevalence of Cr(VI)-induced allergic contact dermatitis is supported
by the findings of Avnstorp (1989) in a study of Danish workers who had
daily contact with wet cement during the manufacture of pre-fabricated
concrete products (Ex. 9-131). Beginning in September of 1981, low
concentrations of ferrous sulfate were added to all cement sold in
Denmark to reduce Cr(VI) to trivalent chromium. Two hundred and twenty
seven workers were examined in 1987 for Cr(VI)-related skin effects.
The findings from these examinations were compared to the results from
190 workers in the same plants who were examined in 1981. The
prevalence of hand eczema had declined from 11.7% to 4.4%, and the
prevalence of Cr(VI) sensitization had declined from 10.5% to 2.6%.
While the two-to four-fold drop in prevalence was statistically
significant, the magnitude of the reduction may be overstated because
the amount of exposure time was less in the 1987 than the 1981 group.
There is also the possibility that other factors, in addition to
ferrous sulfate, may have led to less dermal contact to Cr(VI), such as
greater automation or less construction work. However, the study found
no significant change in the frequency of irritant dermatitis.
    Another study also found lower prevalence of allergic contact
dermatitis among Finish construction workers following the 1987
decision to reduce Cr(VI) content of cement used in Finland to less
than 2 ppm (Ex. 48-8). Ferrous sulfate was typically added to the
cement to meet this requirement. There was a significantly decreased
risk of allergic Cr(VI) contact dermatitis reported to the Finnish
Occupational Disease Registry post-1987 as compared to pre-1987
(OR=0.4, 95% CI: 0.2-0.7) indicating the occurrence of disease dropped
one-third after use of the low Cr(VI) content cement. On the other
hand, the occurrence of irritant dermatitis remained stable throughout
the study period. Time of exposure was not a significant explanatory
variable in the analysis. However, the findings may have been somewhat
confounded by changes in diagnostic procedure over time. The Finnish
study retested patients previously diagnosed with prior patch test
protocols and found several false positives (i.e. false diagnosis of
Cr(VI) allergy).
    In 2003, the Norwegian National Institute of Occupational Health
sponsored an expert peer review of 24

key epidemiological investigations addressing; (1) whether exposure to
wet cement containing water soluble Cr(VI) caused allergic contact
dermatitis, and (2) whether there was a causal association between
reduction of Cr(VI) in cement and reduction in the prevalence of the
disease (Ex. 46-74). The panel of four experts concluded that, despite
the documented limitations of each individual study, the collective
evidence was consistent in supporting ``fairly strong associations
between Cr(VI) content in cement and the occurrence of allergic
dermatitis * * * it seems unlikely that all these associations reported
in the reviewed papers are due to systematic errors only'' (Ex. 46-74,
p. 42).
    Even though the Norwegian panel felt that the available evidence
indicated a relationship between reduced Cr(VI) content of wet cement
and lower occurrence of allergic dermatitis, they stated that the
epidemiological literature was ``not sufficient to conclude that there
is a causal association'' (Ex. 46-74, p. 42). This is somewhat
different than the view expressed in a written June 2002 opinion by the
Scientific Committee on Toxicity, Ecotoxicity and the Environment
(CSTEE) to the European Commission, Directorate for General Health and
Consumer Protection (Ex. 40-10-7). In responding to the question of
whether it is scientifically justified to conclude that cement
containing less than 2 ppm Cr(VI) content could substantially reduce
the risk of skin sensitization, the CSTEE stated that ``the available
information clearly demonstrates that reduction of chromium VI in
cement to less than 2 ppm * * * will reduce the prevalence of allergic
contact eczema in workers'' (Ex. 40-10-7, p. 5)
b. Dermatitis Associated With Cr(VI) From Sources Other Than Cement
    In 1953 the U.S. Public Health Service reported on hazards
associated with the chromium-producing industry in the United States
(Ex. 7-3). Workers were examined for skin effects from Cr(VI) exposure.
Workers' eyes were also examined for possible effects from splashes of
Cr(VI)-containing compounds that had been observed in the plants. Of
the 897 workers examined, 451 had skin ulcers or scars of ulcers.
Seventeen workers were reported to have skin lesions suggestive of
chrome dermatitis. The authors noted that most plants provided adequate
washing facilities, and had facilities for providing clean work
clothes. A statistically significant increase in congestion of the
conjunctiva was also reported in Cr(VI)-exposed workers when compared
with non-exposed workers (38.7% vs. 25.8%).
    In the Baltimore, Maryland chromate production plant examined by
Gibb et al. (2000), a substantial number of workers were reported to
have experienced adverse skin effects (Ex. 31-22-12). The authors
identified a cohort of 2,357 workers first employed at the plant
between 1950 and 1974. Clinic and first aid records were examined to
identify findings of skin conditions. These clinical findings were
identified by a physician as a result of routine examinations or visits
to the medical clinic by members of the cohort. Percentages of the
cohort with various clinical findings were as follows:

Irritated skin: 15.1%
Dermatitis: 18.5%
Ulcerated skin: 31.6%
Conjunctivitis: 20.0%

    A number of factors make these results difficult to interpret. The
reported findings are not specifically related to Cr(VI) exposure. They
may have been the result of other workplace exposures, or non-workplace
factors. The report also indicates the percentage of workers who were
diagnosed with a condition during their tenure at the plant; however,
no information is presented to indicate the expected incidence of these
conditions in a population that is not exposed to Cr(VI).
    Measurements of Cr(VI) air concentrations by job title were used to
estimate worker exposures. Based on these estimates, the authors used a
proportional hazards model to find a statistically significant
correlation (p=0.004) between ulcerated skin and airborne Cr(VI)
exposure. Statistically significant correlations between year of hire
and findings of ulcerated skin and dermatitis were also reported.
Exposures to Cr(VI) in the plant had generally dropped over time.
Median exposure to Cr(VI) at the time of occurrence for most of the
findings was said to be about 10 [mu]g/m\3\ Cr(VI) (reported as 20
[mu]g/m\3\ CrO3). It is unclear, however, what contribution
airborne Cr(VI) exposures may have had to dermal effects. Direct dermal
contact with Cr(VI) compounds in the plant may have been a contributing
factor in the development of these conditions.
    Mean and median times on the job prior to initial diagnosis were
also reported. The mean time prior to diagnosis of skin or eye effects
ranged from 373 days for ulcerated skin to 719 days for irritated skin.
Median times ranged from 110 days for ulcerated skin to 221 days for
conjunctivitis. These times are notable because many workers in the
plant stayed for only a short time. Over 40% worked for less than 90
days. Because these short-term workers did not remain in the workplace
for the length of time that was typically necessary for these effects
to occur, the results of this study may underestimate the incidence
that would occur with a more stable worker population.
    Lee and Goh (1988) examined the skin condition of 37 workers who
maintained chrome plating baths and compared these workers with a group
of 37 control subjects who worked in the same factories but were not
exposed to Cr(VI) (Ex. 35-316). Mean duration of employment as a chrome
plater was 8.1 (SD7.9) years. Fourteen (38%) of the chrome
platers had some occupational skin condition; seven had chrome ulcers,
six had contact dermatitis and one had both. A further 16 (43%) of the
platers had scars suggestive of previous chrome ulcers. Among the
control group, no members had ulcers or scars of ulcers, and three had
dermatitis.
    Where ulcers or dermatitis were noted, patch tests were
administered to determine sensitization to Cr(VI) and nickel. Of the
seven workers with chrome ulcers, one was allergic to Cr(VI). Of the
six workers with dermatitis, two were allergic to Cr(VI) and one to
nickel. The worker with ulceration and dermatitis was not sensitized to
either Cr(VI) or nickel. Although limited by a relatively small study
population, this report clearly indicates that Cr(VI)-exposed workers
face an increased risk of adverse skin effects. The fact that the
majority of workers with dermatitis were not sensitized to Cr(VI)
indicates that irritant factors play an important role in the
development of dermatitis in chrome plating operations.
    Royle (1975) also investigated the occurrence of skin conditions
among workers involved in chrome plating (Ex. 7-50). A questionnaire
survey completed by 997 chrome platers revealed that 21.8% had
experienced skin ulcers, and 24.6% had suffered from dermatitis. No
information was presented to indicate the expected incidence in a
comparable population that was not exposed to Cr(VI). Of the 54 plants
involved in the study, 49 used nickel, another recognized cause of
allergic contact dermatitis.
    The author examined the relationship between the incidence of these
conditions and length of exposure. The plater population was divided
into three groups: those with less than one year of Cr(VI) exposure,
those with one to five years of Cr(VI) exposure, and those with over
five years of Cr(VI) exposure. A statistically significant trend was
found

between length of Cr(VI) exposure and incidence of skin ulcers. The
incidence of dermatitis, on the other hand, bore no relationship to
length of exposure.
    In 1973, researchers from NIOSH reported on the results of a health
hazard investigation of a chrome plating establishment (Ex. 3-5). In
the plating area, airborne Cr(VI) concentrations ranged from less than
0.71 to 9.12 [mu]g/m\3\ (mean 3.24 [mu]g/m\3\; SD=2.48 [mu]g/m\3\). Of
the 37 exposed workers who received medical examinations, five were
reported to have chrome-induced lesions on their hands. Hygiene and
housekeeping practices in this facility were reportedly deficient, with
the majority of workers not wearing gloves, not washing their hands
before eating or leaving the plant, and consuming food and beverages in
work areas.
    Gomes (1972) examined Cr(VI)-induced skin lesions among
electroplaters in Sao Paulo, Brazil (Ex. 9-31). A clinical examination
of 303 workers revealed 88 (28.8%) had skin lesions, while 175 (58.0%)
had skin and mucus membrane lesions. A substantial number of employers
(26.6%) also did not provide personal protective equipment to workers.
The author attributed the high incidence of skin ulcers on the hands
and arms to inadequate personal protective equipment, and lack of
training for employees regarding hygiene practices.
    Fleeger and Deng (1990) reported on an outbreak of skin ulcerations
among workers in a facility where enamel paints containing chromium
were applied to kitchen range parts (Ex. 9-97). A ground coat of paint
was applied to the parts, which were then placed on hooks and
transported through a curing oven. In some cases, small parts were
places on hooks before paint application. Tiny holes in the oven coils
apparently resulted in improper curing of the paint, leaving sharp
edges and a Cr(VI)-containing residue on the hooks. Most of the workers
who handled the hooks reportedly did not wear gloves, because the
gloves were said to reduce dexterity and decrease productivity. As a
result, cuts from the sharp edges allowed the Cr(VI) to penetrate the
skin, leading to ulcerations (Ex. 9-97).
2. Prognosis of Dermal Effects
    Cr(VI)-related dermatitis tends to become more severe and
persistent with continuing exposure. Once established, the condition
may persist even if occupational exposure ceases. Fregert followed up
on cases of occupational contact dermatitis diagnosed over a 10-year
period by a dermatology service in Sweden. Based on responses to
questionnaires completed two to three years after treatment, only 7% of
women and 10% of men with Cr(VI)-related allergic contact dermatitis
were reported to be healed (Ex. 35-322). Burrows reviewed the condition
of patients diagnosed with work-related dermatitis 10-13 years earlier.
Only two of the 25 cases (8%) caused by exposure to cement had cleared
(Ex. 35-323).
    Hogan et al. reviewed the literature regarding the prognosis of
contact dermatitis, and reported that the majority of patients had
persistent dermatitis (Ex. 35-324). It was reported that job changes
did not usually lead to a significant improvement for most patients.
The authors surveyed contact dermatitis experts around the world to
explore their experience with the prognosis of patients suffering from
occupational contact dermatitis of the hands. Seventy-eight percent of
the 51 experts who responded to the survey indicated that chromate was
one of the allergens associated with the worst possible prognosis.
    Halbert et al. reviewed the experience of 120 patients diagnosed
with occupational chromate dermatitis over a 10-year period (Ex. 35-
320). The time between initial diagnosis and the review ranged from a
minimum of six months to a maximum of nine years. Eighty-four (70%) of
patients were reviewed two or more years after initial diagnosis, and
40 (33%) after five years or more. In the majority of cases (78, or
65%), the dermatitis was attributed to work with cement. For the study
population as a whole, 76% had ongoing dermatitis at the time of the
review.
    When the review was conducted, 62 (58%) patients were employed in
the same occupation as when initially diagnosed. Fifty-five (89%) of
these workers continued to suffer from dermatitis. Fifty-eight patients
(48%) changed occupations after their initial diagnosis. Each of these
individuals indicated that they had changed occupations because of
their dermatitis. In spite of the change, dermatitis persisted in 40
members of this group (69%).
    Lips et al. found a somewhat more favorable outcome among 88
construction workers with occupational chromate dermatitis who were
removed from Cr(VI) exposure (Ex. 35-325). Follow-up one to five years
after removal indicated that 72% of the patients no longer had
dermatitis. The authors speculated that this result might be due to
strict avoidance of Cr(VI) contact. Nonetheless, the condition
persisted in a substantial portion of the affected population.
3. Thresholds for Dermal Effects
    In a response to OSHA's RFI submitted on behalf of the Chrome
Coalition, Exponent indicated that the findings of Fowler et al. (1999)
and others provide evidence of a threshold for elicitation of allergic
contact dermatitis (Ex. 31-18-1, p. 27). Exponent also stated that
because chrome ulcers did not develop in the Fowler et al. study,
``more aggressive'' exposures appear to be necessary for the
development of chrome ulcers.
    The Fowler et al. study involved the dermal exposure of 26
individuals previously sensitized to Cr(VI) who were exposed to water
containing 25 to 29 mg/L Cr(VI) as potassium dichromate (pH 9.4) (Ex.
31-18-5). Subjects immersed one arm in the Cr(VI) solution, while the
other arm was immersed in an alkaline buffer solution as a control.
Exposure lasted for 30 minutes and was repeated on three consecutive
days. Based on examination of the skin, the authors concluded that the
skin response experienced by subjects was not consistent with either
irritant or allergic contact dermatitis.
    The exposure scenario in the Fowler et al. study, however, does not
take into account certain skin conditions often encountered in the
workplace. While active dermatitis, scratches, and skin lesions served
as criteria for excluding both initial and continuing participation in
the study, it is reasonable to expect that individuals with these
conditions will often continue to work. Cr(VI)-containing mixtures and
compounds used in the workplace may also pose a greater challenge to
the integrity of the skin than the solution used by Fowler et al. Wet
cement, for example, may have a pH higher than 9.4, and may be capable
of abrading or otherwise damaging the skin. As damaged skin is liable
to make exposed workers more susceptible to Cr(VI)-induced skin
effects, the suggested threshold is likely to be invalid. The absence
of chrome ulcers in the Fowler et al. study is not unexpected, because
subjects with ``fissures or lesions'' on the skin were excluded from
the study (Ex. 31-18-5). As discussed earlier, chrome ulcers are not
believed to occur on intact skin.
4. Conclusions
    OSHA believes that adverse dermal effects from exposure to Cr(VI),
including irritant contact dermatitis, allergic contact dermatitis, and
skin ulceration, have been firmly established. The available evidence
is not sufficient to relate these effects to any given Cr(VI) air
concentration. Rather, it appears that direct dermal contact with
Cr(VI) is the

most relevant factor in the development of dermatitis and ulcers. Based
on the findings of Gibb et al. (Ex. 32-22-12) and U.S. Public Health
Service (Ex. 7-3), OSHA believes that conjunctivitis may result from
direct eye contact with Cr(VI).
    OSHA does not believe that the available evidence is sufficient to
establish a threshold concentration of Cr(VI) below which dermal
effects will not occur in the occupational environment. This finding is
supported not only by the belief that the exposure scenario of Fowler
et al. is not consistent with occupational exposures, but by experience
in the workplace as well. As summarized by Flyvholm et al. (1996),
numerous reports have indicated that allergic contact dermatitis occurs
in cement workers exposed to Cr(VI) concentrations below the threshold
suggested by Fowler et al. (1999). OSHA considers the evidence of
Cr(VI)-induced allergic contact dermatitis in these workers to indicate
that the threshold for elicitation of response suggested by Fowler et
al. (1999) is not applicable to the occupational environment.

E. Other Health Effects

    OSHA has examined the possibility of health effect outcomes
associated with Cr(VI) exposure in addition to such effects as lung
cancer, nasal ulcerations and perforations, occupational asthma, and
irritant and allergic contact dermatitis. Unlike the Cr(VI)-induced
toxicities cited above, the data on other health effects do not
definitively establish Cr(VI)-related impairments of health from
occupational exposure at or below the previous OSHA PEL.
    There is some positive evidence that workplace inhalation of Cr(VI)
results in gastritis and gastrointestinal ulcers, especially at high
exposures (generally over OSHA's previous PEL) (Ex. 7-12). This is
supported by ulcerations in the gastrointestinal tract of mice
breathing high Cr(VI) concentration for long periods (Ex. 10-8). Other
studies reported positive effects but significant information was not
reported or the confounders made it difficult to draw positive
conclusions (Ex. 3-84; Sassi 1956 as cited in Ex. 35-41). Other studies
reported negative results (Exs. 7-14; 9-135).
    Likewise, several studies reported increases in renal proteins in
the urine of chromate production workers and chrome platers (Exs. 35-
107; 5-45; 35-105; 5-57). The Cr(VI) air levels recorded in these
workers were usually below the previous OSHA PEL (Exs. 35-107; 5-45).
Workers with the highest urinary chromium levels tended to also have
the largest elevations in renal markers (Ex. 35-107). One study
reported no relationship between chromium in urine and renal function
parameters, no relationship with age or with duration of exposure, and
no relationship between the presence of chromium skin ulcers and
chromium levels in urine or renal function parameters (Ex. 5-57). In
most studies, the elevated renal protein levels were restricted to only
one or two proteins out of several examined per study, generally
exhibited small increases (Ex. 35-105) and the effects appeared to be
reversible (Ex. 5-45). In addition, it has been stated that low
molecular weight proteinuria can occur from other reasons and cannot by
itself be considered evidence of chronic renal disease (Ex. 35-195).
Other human inhalation studies reported no changes in renal markers
(Exs. 7-27; 35-104). Animal inhalation studies did not report kidney
damage (Exs. 9-135; 31-18-11; 10-11; 31-18-10; 10-10). Some studies
with Cr(VI) administered by drinking water or gavage were positive for
increases in renal markers as well as some cell and tissue damage (Exs.
9-143; 11-10). However, it is not clear how to extrapolate such
findings to workers exposed to Cr(VI) via inhalation. Well-designed
studies of effects in humans via ingestion were not found.
    OSHA did not find information to clearly and sufficiently
demonstrate that exposures to Cr(VI) result in significant impairment
to the hepatic system. Two European studies, positive for an excess of
deaths from cirrhosis of the liver and hepatobiliarity disorders, were
not able to separate chromium exposures from exposures to the many
other substances present in the workplace. The authors also could not
rule out the role of alcohol use as a possible contributor to the
disorder (Ex. 7-92; Sassi as cited in Ex. 35-41). Other studies did not
report any hepatic abnormalities (Exs. 7-27; 10-11).
    The reproductive studies showed mixed results. Some positive
reproductive effects occurred in some welding studies. However, it is
not clear that Cr(VI) is the causative agent in these studies (Exs. 35-
109; 35-110; 35-108; 35-202; 35-203). Other positive studies were
seriously lacking in information. Information was not given on
exposures, the nature of the reproductive complications, or the women's
tasks (Shmitova 1980, 1978 as cited in Ex. 35-41, p. 52). ATSDR states
that because these studies were generally of poor quality and the
results were poorly reported, no conclusions can be made on the
potential for chromium to produce adverse reproductive effects in
humans (Ex. 35-41, p. 52). In animal studies, where Cr(VI) was
administered through drinking water or diet, positive developmental
effects occurred in offspring (Exs. 9-142; 35-33; 35-34; 35-38).
However, the doses administered in drinking water or given in the diet
were high (i.e., 250, 500, and 750 ppm). Furthermore, strong studies
showing reproductive or developmental effects in other situations where
employees were working exclusively with Cr(VI) were not found. In fact,
the National Toxicology Program (NTP) (Exs. 35-40; 35-42; 35-44)
conducted an extensive multigenerational reproductive assessment by
continuous breeding where the chromate was administered in the diet.
The assessment yielded negative results (Exs. 35-40; 35-42; 35-44).
Animal inhalation studies were also negative (Exs. 35-199; 9-135; 10-
10; Glaser 1984 as cited in Ex. 31-22-33;). Thus, it cannot be
concluded that Cr(VI) is a reproductive toxin for normal working
situations.

VI. Quantitative Risk Assessment

A. Introduction

    The Occupational Safety and Health (OSH) Act and some landmark
court cases have led OSHA to rely on quantitative risk assessment,
where possible, to support the risk determinations required to set a
permissible exposure limit (PEL) for a toxic substance in standards
under the OSH Act. Section 6(b)(5) of the Act states that ``The
Secretary [of Labor], in promulgating standards dealing with toxic
materials or harmful agents under this subsection, shall set the
standard which most adequately assures, to the extent feasible, on the
basis of the best available evidence, that no employee will suffer
material impairment of health or functional capacity even if such
employee has regular exposure to the hazard dealt with by such standard
for the period of his working life.'' (29 U.S.C. 651 et seq.)
    In a further interpretation of the risk requirements for OSHA
standard setting, the United States Supreme Court, in the 1980
``benzene'' decision, (Industrial Union Department, AFL-CIO v. American
Petroleum Institute, 448 U.S. 607 (1980)) ruled that the OSH Act
requires that, prior to the issuance of a new standard, a determination
must be made that there is a significant risk of material impairment of
health at the existing PEL and that issuance of a new standard will
significantly reduce or eliminate that risk. The Court stated that
``before he can promulgate any

permanent health or safety standard, the Secretary is required to make
a threshold finding that a place of employment is unsafe in the sense
that significant risks are present and can be eliminated or lessened by
a change in practices'' [448 U.S. 642]. The Court also stated ``that
the Act does not limit the Secretary's power to require the elimination
of significant risks'' [488 U.S. 644]. While the Court indicated that
the use of quantitative risk analysis was an appropriate means to
establish significant risk, they made clear that ``OSHA is not required
to support its finding that a significant risk exists with anything
approaching scientific certainty.''
    The Court in the Cotton Dust case, (American Textile Manufacturers
Institute v. Donovan, 452 U.S. 490 (1981)) found that Section 6(b)(5)
of the OSH Act places benefits to worker health above all other
considerations except those making attainment of the health benefits
unachievable and, therefore, only feasibility analysis of OSHA health
standards is required and not cost-benefit analysis. It reaffirmed its
previous position in the ``benzene'' case, however, that a risk
assessment is not only appropriate but should be used to identify
significant health risk in workers and to determine if a proposed
standard will achieve a reduction in that risk. Although the Court did
not require OSHA to perform a quantitative risk assessment in every
case, the Court implied, and OSHA as a matter of policy agrees, that
assessments should be put into quantitative terms to the extent
possible.
    The determining factor in the decision to perform a quantitative
risk assessment is the availability of suitable data for such an
assessment. As reviewed in section V.B. on Carcinogenic Effects, there
are a substantial number of occupational cohort studies that reported
excess lung cancer mortality in workers exposed to Cr(VI) in several
industrial operations. Many of these found that workers exposed to
higher levels of airborne Cr(VI) for a longer period of time had
greater standardized mortality ratios (SMRs) for lung cancer.
    OSHA believes that two recently studied occupational cohorts by
Gibb et al. (Ex. 31-22-11) and Luippold et al. (Ex. 33-10) have the
strongest data sets on which to quantify lung cancer risk from
cumulative Cr(VI) exposure (i.e., air concentration x exposure
duration). A variety of exposure-response models were fit to these
data, including linear relative risk, quadratic relative risk, log-
linear relative risk, additive risk, and Cox proportional hazards
models. Using a linear relative risk model on these data to predict
excess lifetime risk, OSHA estimated that the lung cancer risk from a
45 year occupational exposure to Cr(VI) at an 8-hour TWA at the
previous PEL of 52 [mu]g/m\3\ is 101 to 351 excess deaths per 1000.
Quantitative lifetime risk estimates from a working lifetime exposure
at several lower alternative PELs under consideration by the Agency
were also estimated. The sections below discuss the selection of the
appropriate data sets and risk models, the estimation of lung cancer
risks based on the selected data sets and models, the uncertainty in
the risk estimates, and the key issues that were raised in comments
received during the public hearing process.
    A preliminary quantitative risk assessment was previously published
in the Notice of Proposed Rulemaking (69 FR at 59306, 10/4/2004). This
was peer-reviewed by three outside experts in the fields of
occupational epidemiology and risk assessment. Their comments were
discussed in the NPRM (69 FR at 59385-59388). They commented on the
suitability of several occupational data sets for exposure-response
analysis, the choice of exposure metric and risk model, the
appropriateness of the risk estimates, and the characterization of key
issues and uncertainties. The reviewers agreed that the soluble
chromate production cohorts described by Gibb et al. and Luippold et
al. provided the strongest data sets for quantitative risk assessment.
They concurred that a linear model using cumulative exposure based on
time-weighted average Cr(VI) air concentrations by job title and
employment history was the most reasonable risk assessment approach.
The experts showed less enthusiasm for average monthly Cr(VI) air
concentrations as an appropriate exposure metric or for an exposure
threshold below which there is no lung cancer risk. They found the
range of excess lifetime lung cancer risks presented by OSHA to be
sound and reasonable. They offered suggestions regarding issues such as
the impact of cigarette smoking and the healthy worker effect on the
assessment of risk. OSHA revised the preliminary quantitative risk
assessment in several respects based on these peer review comments.
    In contrast to the more extensive occupational cohort data on
Cr(VI) exposure-response, data from experimental animal studies are
less suitable for quantitative risk assessment of lung cancer. Besides
the obvious species difference, most of the animal studies administered
Cr(VI) to the respiratory tract by less relevant routes, such as
instillation or implantation. The few available inhalation studies in
animals were limited by a combination of inadequate exposure levels,
abbreviated durations, and small numbers of animals per dose group.
Despite these limitations, the animal data do provide semi-quantitative
information with regard to the relative carcinogenic potency of
different Cr(VI) compounds. A more detailed discussion can be found in
sections V.B.7 and V.B.9.
    The data that relate non-cancer health impairments, such as damage
to the respiratory tract and skin, to Cr(VI) exposure are also not well
suited for quantitative assessment. There are some data from cross-
sectional studies and worker surveys that group the prevalence and
severity of nasal damage by contemporary time-weighted average (TWA)
Cr(VI) air measurements. However, there are no studies that track
either incidence or characterize exposure over time. Nasal damage is
also more likely influenced by shorter-term peak exposures that have
not been well characterized. While difficult to quantify, the data
indicate that the risk of damage to the nasal mucosa will be
significantly reduced by lowering the previous PEL, discussed further
in section VII on Significance of Risk.
    There are even less suitable exposure-response data to assess risk
for other Cr(VI)-induced impairments (e.g., mild renal damage,
gastrointestinal ulceration). With the possible exception of
respiratory tract effects (e.g., nasal damage, occupational asthma),
the risk of non-cancer adverse effects that result from inhaling Cr(VI)
are expected to be very low, except as a result of long-term regular
airborne exposure around or above the previous PEL (52 [mu]g/m\3\).
Since the non-cancer effects occur at relatively high Cr(VI) air
concentrations, OSHA has concluded that lowering the PEL to reduce the
risk of developing lung cancer over a working lifetime will also
eliminate or reduce the risk of developing these other health
impairments. As discussed in section V.E., adverse effects to the skin
primarily result from dermal rather than airborne exposure.

B. Study Selection

    The more than 40 occupational cohort studies reviewed in Section
VI.B on carcinogenic effects were evaluated to determine the adequacy
of the exposure-response information for the quantitative assessment of
lung cancer risk associated with Cr(VI) exposure. The key criteria were
data that allowed for estimation of input variables,

specifically levels of exposure and duration of exposure (e.g.,
cumulative exposure in mg/m\3\-yr); observed numbers of cancers (deaths
or incident cases) by exposure category; and expected (background)
numbers of cancer deaths by exposure category.
    Additional criteria were applied to evaluate the strengths and
weaknesses of the available epidemiological data sets. Studies needed
to have well-defined cohorts with identifiable cases. Features such as
cohort size and length of follow-up affect the ability of the studies
to detect any possible effect of Cr(VI) exposure. Potential confounding
of the responses due to other exposures was considered. Study
evaluation also considered whether disease rates from an appropriate
reference population were used to derive expected numbers of lung
cancers. One of the most important factors in study evaluation was the
ascertainment and use of exposure information (i.e., well-documented
historical exposure data). Both level and duration of exposure are
important in determining cumulative dose, and studies are often
deficient with respect to the availability or use of such information.
    Two recently studied cohorts of chromate production workers, the
Gibb cohort and the Luippold cohort, were found to be the strongest
data sets for quantitative assessment (Exs. 31-22-11; 33-10). Of the
various studies, these two had the most extensive and best documented
Cr(VI) exposures spanning three or four decades. Both cohort studies
characterized observed and expected lung cancer mortality and reported
a statistically significant positive association between lung cancer
risk and cumulative Cr(VI) exposure. For the remainder of this preamble
the Gibb and Luippold cohorts are referred to as the ``preferred
cohorts'', denoting that they are the cohorts used to derive OSHA's
model of lung cancer risk from exposure to Cr(VI).
    Four other cohorts (Mancuso, Hayes et al., Gerin et al., and
Alexander et al.) had less satisfactory data for quantitative
assessments of lung cancer risk (Exs. 7-11; 23; 7-14; 7-120; 31-16-3).
These cohorts include chromate production workers, stainless steel
welders, and aerospace manufacturing workers. While the lung cancer
response in these cohorts was stratified across multiple exposure
groups, there were limitations to these data that affected their
reliability for quantitative risk assessment. OSHA therefore did not
consider them to be preferred cohorts (i.e., they were not used to
derive OSHA's model of lung cancer risk from exposure to Cr(VI)).
However, OSHA believes that quantitative analysis of these cohorts
provides valuable information to the risk assessment, especially for
the purpose of comparison with OSHA's risk model based on the preferred
Gibb and Luippold cohorts. Analyses based on the Mancuso, Hayes et al.,
Gerin et al., and Alexander et al. cohorts, referred to as ``additional
cohorts'' for the remainder of this preamble, were compared with the
assessments based on the Gibb and Luippold cohorts. The strengths and
weaknesses of all six cohorts as a basis for exposure-response analysis
are discussed in more detail below.
1. Gibb Cohort
    The Gibb et al. study was a particularly strong study for
quantitative risk assessment, especially in terms of cohort size and
historical exposure data (Exs. 31-22-11; 33-11). Gibb et al. studied an
updated cohort from the same Baltimore chromate production plant
previously studied by Hayes et al. (see section VI.B.4). The cohort
included 2357 male workers (white and non-white) first employed between
1950 and 1974. Follow-up was through the end of 1992 for a total of
70,736 person-years and an average length of 30 years per cohort
member. Smoking status and amount smoked in packs per day at the start
of employment was available for the majority of the cohort members.
    A significant advantage of the Gibb data was the availability of a
large number of personal and area sampling measurements from a variety
of locations and job titles which were collected over the years during
which the cohort members were exposed (from 1950 to 1985, when the
plant closed). Using these concentration estimates, a job exposure
matrix was constructed giving annual average exposures by job title.
Based on the job exposure matrix and work histories for the cohort
members, Gibb et al. computed the person-years of observation, the
observed numbers of lung cancer deaths, and the expected numbers of
lung cancer deaths categorized by cumulative Cr(VI) exposure and age of
death. They found that cumulative Cr(VI) exposure was a significant
predictor of lung cancer risk over the exposure range of 0 to 2.76
(meanSD = 0.702.75) mg/m\3\-yr. This included a
greater than expected number of lung cancer deaths among relatively
young workers. For example, chromate production workers between 40 and
50 years of age with mean cumulative Cr(VI) exposure of 0.41 mg
CrO3/m\3\-yr (equivalent to 0.21 mg Cr(VI)/m\3\-yr) were
about four times more likely to die of lung cancer than a State of
Maryland resident of similar age (Ex. 31-22-11, Table V).
    The data file containing the demographic, exposure, smoking, and
mortality data for the individual cohort members was made available to
OSHA (Ex. 295). These data were used in several reanalyses to produce
several different statistical exposure-response models and to explore
various issues raised in comments to OSHA, such as the use of linear
and nonlinear exposure-response models, the difference between modern
and historical levels of Cr(VI) exposure, and the impact of including
or excluding short-term workers from the exposure-response analysis.
The Agency's access to the dataset and to reanalyses of it performed by
several different analysts has been a tremendous advantage in its
consideration of these and other issues in the development of the final
risk assessment.
2. Luippold Cohort
    The other well-documented exposure-response data set comes from a
second cohort of chromate production workers. Luippold et al. studied a
cohort of 482 predominantly white, male employees who started work
between 1940 and 1972 at the same Painesville, Ohio plant studied
earlier by Mancuso (Ex. 33-10) (see subsection VI.B.3). Mortality
status was followed through 1997 for a total of 14,048 person-years.
The average worker had 30 years of follow-up. Cr(VI) exposures for the
Luippold cohort were based on 21 industrial hygiene surveys conducted
at the plant between 1943 and 1971, yielding a total of more than 800
area samples (Ex. 35-61). A job exposure matrix was computed for 22
exposure areas for each month of plant operation starting in 1940 and,
coupled with detailed work histories available for the cohort members,
cumulative exposures were calculated for each person-year of
observation. Luippold et al. found significant dose-related trends for
lung cancer SMRs as a function of year of hire, duration of employment,
and cumulative Cr(VI) exposure. Risk assessments on the Luippold et al.
study data performed by Crump et al. had access to the individual data
and, therefore, had the best basis for analysis of this cohort (Exs.
31-18-1; 35-205; 35-58).
    While the Luippold cohort was smaller and less racially diverse
than the Gibb cohort, the workforce contained fewer transient, short-
term employees. The Luippold cohort consisted entirely of workers
employed over one year. Fifty-five percent worked

for more than five years. In comparison, 65 percent of the Gibb cohort
worked for less than a year and 15 percent for more than five years at
the Baltimore plant. There was less information about the smoking
behavior (smoking status available for only 35 percent of members) of
the Luippold cohort than the Gibb cohort.
    One aspect that the Luippold cohort had in common with the Gibb
cohort was extensive and well-documented air monitoring of Cr(VI). The
quality of exposure information for both the Gibb and Luippold cohorts
was considerably better than that for the Mancuso, Hayes et al., Gerin
et al., and Alexander et al. cohorts. The cumulative Cr(VI) exposures
for the Luippold cohort, which ranged from 0.003 to 23 (mean< plus-
minus>SD = 1.582.50) mg Cr(VI)/m\3\-yr, were generally
higher but overlapped those of the Gibb cohort. The use of individual
work histories to define exposure categories and presentation of mean
cumulative doses in the exposure groups provided a strong basis for a
quantitative risk assessment. The higher cumulative exposure range and
the longer work duration of the Luippold cohort serve to complement
quantitative data available on the Gibb cohort.
3. Mancuso Cohort
    Mancuso (Ex. 7-11) studied the lung cancer incidence of an earlier
cohort of 332 white male employees drawn from the same plant in
Painesville, Ohio that was evaluated by the Luippold group. The Mancuso
cohort was first employed at the facility between 1931 and 1937 and
followed up through 1972, when the plant closed. Mancuso (Ex. 23) later
extended the follow-up period through 1993, yielding a total of 12,881
person-years of observation for an average length of 38.8 years and a
total of 66 lung cancer deaths. Since the Mancuso workers were first
employed in the 1930s and the Luippold workers were first employed
after 1940, the two cohorts are completely different sets of
individuals.
    A major limitation of the Mancuso study is the uncertainty of the
exposure data. Mancuso relied exclusively on the air monitoring
reported by Bourne and Yee (Ex. 7-98) conducted over a single short
period of time during 1949. Bourne and Yee presented monitoring data as
airborne insoluble chromium, airborne soluble chromium, and total
airborne chromium by production department at the Painesville plant.
The insoluble chromium was probably Cr(III) compounds with some
slightly water-soluble and insoluble chromates. The soluble chromium
was probably highly water-soluble Cr(VI). Mancuso (Exs. 7-11; 23)
calculated cumulative exposures (mg/m\3\-yr) for each cohort member
based on the 1949 mean chromium concentrations, by production
department, under the assumption that those levels reflect exposures
during the entire duration of employment for each cohort member, even
though employment may have begun as early as 1931 and may have extended
to 1972. Due to the lack of air measurements spanning the full period
of worker exposure and the lack of adequate methodology to distinguish
chromium valence states (i.e., Cr(VI) vs. Cr(III)), the exposure data
associated with the Mancuso cohort were not as well characterized as
data from the Luippold or Gibb cohorts.
    Mancuso (Exs. 7-11; 23)reported cumulative exposure-related
increases in age-adjusted lung cancer death rates for soluble,
insoluble, or total chromium. Within a particular range of exposures to
insoluble chromium, lung cancer death rates also tended to increase
with increasing total cumulative chromium. However, the study did not
report whether these tendencies were statistically significant, nor did
it report the extent to which exposures to soluble and insoluble
chromium were correlated. Thus, it is possible that the apparent
relationship between insoluble chromium (e.g., primarily Cr(III)) and
lung cancer may have arisen because both insoluble chromium
concentrations and lung cancer death rates were positively correlated
with Cr(VI) concentrations. Further discussion with respect to
quantitative risk estimation from the Mancuso cohort is provided in
section VI.E.1 on additional risk assessments.
4. Hayes Cohort
    Hayes et al. (Ex. 7-14) studied a cohort of employees at the same
chromate production site in Baltimore examined by Gibb et al. The Hayes
cohort consisted of 2101 male workers who were first hired between 1945
and 1974, excluding those employed for less than 90 days. The Gibb
cohort had different but partially overlapping date criteria for first
employment (1950-1974) and no 90 day exclusion. Hayes et al. reported
SMRs for respiratory tract cancer based on workers grouped by time of
hire, employment duration, and high or low exposure groups. Workers who
had ever worked at an older plant facility and workers whose location
of employment could not be determined were combined into a single
exposure group referred to as ``high or questionable'' exposure.
Workers known to have been employed exclusively at a newer renovated
facility built in 1950 and 1951 were considered to have had ``low''
exposure. A dose-response was observed in the sense that higher SMRs
for respiratory cancer were observed among long-term workers (workers
who had worked for three or more years) than among short-term workers.
    Hayes et al. did not quantify occupational exposure to Cr(VI) at
the time the cohort was studied, but Braver et al. (Ex. 7-17) later
estimated average cumulative soluble chromium (presumed by the authors
to be Cr(VI)) exposures for four subgroups of the Hayes cohort first
employed between 1945 and 1959. The TWA Cr(VI) concentrations were
determined from a total of 555 midget impinger air measurements that
were collected at the older plant from 1945 to 1950. The cumulative
exposures for the subgroups were estimated from the yearly average
Cr(VI) exposure for the entire plant and the subgroups' average
duration of employment rather than job-specific Cr(VI) concentrations
and individual work histories. Such ``group level'' estimation of
cumulative exposure is less appropriate than the estimation based on
individual experiences as was done for the Gibb and Luippold cohorts.
    A more severe limitation of this study is that exposures attributed
to many workers in the newly renovated facility at the Baltimore site
throughout the 1950s were based on chromium measurements from an
earlier period (i.e., 1949-1950) at an older facility. Samples
collected at the new facility and reviewed by Gibb et al. (Exs. 25, 31-
22-12) show that the exposures in the new facility were substantially
lower than assumed by Braver et al. Braver et al. (Ex. 7-17) discussed
a number of other potential sources of uncertainty in the Cr(VI)
exposure estimates, such as the possible conversion to Cr(III) during
sample collection and the likelihood that samples may have been
collected mainly in potential problem areas.
5. Gerin Cohort
    Gerin et al. (Ex. 7-120) developed a job exposure matrix that was
used to estimate cumulative Cr(VI) exposures for male stainless steel
welders who were part of the International Agency for Research on
Cancer's (IARC) multi-center historical cohort study (Ex. 7-114). The
IARC cohort included 11,092 welders. However, the number of cohort
members who were stainless steel welders, for which Cr(VI) exposures
were estimated, could not be determined from their report. Gerin et al.
used occupational hygiene surveys reported in the published literature,
including a limited amount of data collected from 8 of the 135
companies

that employed welders in the cohort, to estimate typical eight-hour TWA
Cr(VI) breathing zone concentrations for various combinations of
welding processes and base metal. The resulting exposure matrix was
then combined with information about individual work history, including
time and length of employment, type of welding, base metal welded, and
information on typical ventilation status for each company (e.g.,
confined area, use of local exhaust ventilation, etc.) to estimate the
cumulative Cr(VI) exposure. Individual work histories were not
available for about 25 percent of the stainless steel welders. In these
cases, information was assumed based on the average distribution of
welding practices within the company. The lack of Cr(VI) air
measurements from most of the companies in the study and the
limitations in individual work practice information for this cohort
raise questions concerning the accuracy of the exposure estimates.
    Gerin et al. reported no upward trend in lung cancer mortality
across four cumulative Cr(VI) exposure categories for stainless steel
welders, each accumulating between 7,000 and 10,000 person-years of
observation. The welders were also known to be exposed to nickel,
another potential lung carcinogen. Co-exposure to nickel may obscure or
confound the Cr(VI) exposure-response relationship. As discussed
further in Sections VI.E.3 and VI.G.4, exposure misclassification in
this cohort may obscure an exposure-response relationship. This is the
primary reason that the Gerin et al. cohort was not considered a
preferred cohort (i.e., it was not used to derive OSHA's quantitative
risk estimates), although a quantitative analysis of this cohort was
performed for comparison with the preferred cohorts.
6. Alexander Cohort
    Alexander et al. (Ex. 31-16-3) conducted a retrospective cohort
study of 2429 aerospace workers employed in jobs entailing chromate
exposure (e.g., spray painting, sanding/polishing, chrome plating,
etc.) between 1974 and 1994. The cohort included workers employed as
early as 1940. Follow-up time was short, averaging 8.9 years per cohort
member; in contrast, the Gibb and Luippold cohorts accumulated an
average 30 or more years of follow-up. Long-term follow-up of cohort
members is particularly important for determining the risk of lung
cancer, which typically has an extended latency period of twenty years
or more.
    Industrial hygiene data collected between 1974 and 1994 were used
to classify jobs in categories of ``high'' exposure, ``moderate''
exposure, or ``low'' exposure to Cr(VI). The use of respiratory
protection was accounted for when setting up the job exposure matrix.
These exposure categories were assigned summary TWA concentrations and
combined with individual job history records to estimate cumulative
exposures for cohort members over time. As further discussed in section
VI.E.4, it was not clear from the study whether exposures are expressed
in units of Cr(VI) or chromate (CrO3). Exposures occurring
before 1974 were assumed to be at TWA levels assigned to the interval
from 1974 to 1985.
    Alexander et al. presented lung cancer incidence data for four
cumulative chromate exposure categories based on worker duration and
the three (high, moderate, low) exposure levels. Lung cancer incidence
rates were determined using a local cancer registry, part of the
National Cancer Institute (NCI) Surveillance Epidemiology and End
Results (SEER) program. The authors reported no positive trend in lung
cancer incidence with increasing Cr(VI) exposure. Limitations of this
cohort study include the young age of the cohort members (median = 42)
and lack of information on smoking. As discussed above, the follow-up
time (average <  9 years) was probably too short to capture lung cancers
resulting from Cr(VI) exposure. Finally, the available Cr(VI) air
measurement data did not span the entire employment period of the
cohort (e.g., no data for 1940 to 1974) and was heavily grouped into a
relatively small number of ``summary'' TWA concentrations that may not
have fully captured individual differences in workplace exposures to
Cr(VI). For the above reasons, in particular the insufficient follow-up
time for most cohort members, the Alexander cohort was not considered a
preferred dataset for OSHA's quantitative risk analysis. However, a
quantitative analysis of this cohort was performed for comparison with
the preferred cohorts.
7. Studies Selected for the Quantitative Risk Assessment
    The epidemiologic database is quite extensive and contains several
studies with exposure and response data that could potentially be used
for quantitative risk assessment. OSHA considers certain studies to be
better suited for quantitative assessment than others. The Gibb and
Luippold cohorts are the preferred sources for quantitative risk
assessment because they are large, have extensive follow-up, and have
documentation of historical Cr(VI) exposure levels superior to the
Mancuso, Hayes, Gerin and Alexander cohorts. In addition, analysts have
had access to the individual job histories of cohort members and
associated exposure matrices. OSHA's selection of the Gibb and Luippold
cohorts as the best basis of exposure-response analysis for lung cancer
associated with Cr(VI) exposure was supported by a variety of
commenters, including for example NIOSH (Tr. 314; Ex. 40-10-2, p. 4),
EPRI (Ex. 38-8, p.6), and Exponent (Ex. 38-215-2, p. 15). It was also
supported by the three external peer reviewers who reviewed OSHA's
preliminary risk assessment, Dr. Gaylor (Ex. 36-1-4-1, p. 24), Dr.
Smith (Ex. 36-1-4-2 p. 28), and Dr. Hertz-Picciotto (Ex. 36-1-4-4, pp.
41-42).
    The Mancuso cohort and the Hayes cohort were derived from workers
at the same plants as Luippold and Gibb, respectively, but have
limitations associated with the reporting of quantitative information
and exposure estimates that make them less suitable for risk
assessment. Similarly, the Gerin and Alexander cohorts are less
suitable, due to limitations in exposure estimation and short follow-
up, respectively. For these reasons, OSHA did not rely upon the
Mancuso, Hayes, Gerin, and Alexander cohorts to derive its exposure-
response model for the risk of lung cancer from Cr(VI).
    Although the Agency did not rely on the Mancuso, Hayes, Gerin, and
Alexander studies to develop its exposure-response model, OSHA believes
that evaluating risk among several different worker cohorts and
examining similarities and differences between them adds to the overall
completeness and quality of the assessment. The Agency therefore
analyzed these datasets and compared the results with the preferred
Gibb and Luippold cohorts. This comparative analysis is discussed in
Section VI.E. In light of the extensive worker exposure-response data,
there is little additional value in deriving quantitative risk
estimates from tumor incidence results in rodents, especially
considering the concerns with regard to route of exposure and study
design.
    OSHA received a variety of public comments regarding the overall
quality of the Gibb and Luippold cohorts and their suitability as the
preferred cohorts in OSHA's quantitative risk analysis. Some commenters
raised concerns about the possible impact of short-term workers in the
Gibb cohort on the risk assessment (Tr. 123; Exs. 38-106, p. 10, 21;
40-12-5, p. 9). The Gibb cohort's inclusion of many workers employed
for short periods of time was cited as a

``serious flaw'' by one commenter, who suggested that many lung cancers
among short-term workers in the study were caused by unspecified other
factors (Ex. 38-106, p. 10, p. 21). Another commenter stated that the
Davies cohort of British chromate production workers ``gives greater
credence to the Painesville cohort as it showed that brief exposures
(as seen in a large portion of the Baltimore cohort) did not have an
increased risk of lung cancer'' (Ex. 39-43, p. 1). However, separate
analyses of the short-term (<  1 year employment) and longer-term ( 1
year) Gibb cohort members indicated that restriction of the cohort to
workers with tenures of at least one year did not substantially impact
estimates of excess lung cancer mortality (Ex. 31-18-15-1 , p. 29). At
the public hearing, Ms. Deborah Proctor of Exponent, Inc. stated that
``the short term workers did not affect the results of the study'' (Tr.
1848). OSHA agrees with Ms. Proctor's conclusion, and does not believe
that the inclusion of short term workers in the Gibb cohort is a source
of substantial uncertainty in the Agency's risk estimates.
    Some commenters expressed concern that the Gibb study did not
control for smoking (Exs. 38-218, pp. 20-21; 38-265, p. 28; 39-74, p.
3). However, smoking status at the time of employment was ascertained
for approximately 90% of the cohort (Ex. 35-435) and was used in
statistical analyses by Gibb et al., Environ Inc., and Exponent Inc. to
adjust for the effect of smoking on lung cancer in the cohort (Exs. 25;
31-18-15-1; 35-435). NIOSH performed similar analyses using more
detailed information on smoking level (packs per day) that was
available for 70% of the cohort (Ex. 35-435, p.1100). OSHA believes
that these analyses appropriately addressed the potential confounding
effect of smoking in the Gibb cohort. Issues and analyses related to
smoking are further discussed in Section VI.G.3.
    Other issues and uncertainties raised about the Gibb and Luippold
cohorts include a lack of information necessary to estimate deposited
dose of Cr(VI) for workers in either cohort and a concern that the
Luippold exposure data were based on exposures to ``airborne total
soluble and insoluble chromium* * * rather than exposures to Cr(VI)''
(Ex. 38-218, pp. 20-21). However, the exposure estimates for the
Luippold (2003) cohort were recently developed by Proctor et al. using
measurements of airborne Cr(VI), not the total chromium measurements
used previously in Mancuso et al.'s analysis (Exs. 35-58, p. 1149; 35-
61). And, while it is true that the Gibb and Luippold (2003) datasets
do not lend themselves to construction of deposited dose measures, the
extensive Cr(VI) air monitoring data available on these cohorts are
more than adequate for quantitative risk assessment. In the case of the
Gibb cohort, the exposure dataset is extraordinarily comprehensive and
well-documented (Tr. 709-710; Ex. 44-4, p.2), even ``exquisite''
according to one NIOSH expert (Tr. 312). Further discussion of the
quality and reliability of the Gibb and Luippold (2003) exposure data
and related comments appears in Section VI.G.1.
    OSHA received several comments regarding a new epidemiological
study conducted by Environ, Inc. for the Industrial Health Foundation,
Inc. of workers hired after the institution of process changes and
industrial hygiene practices designed to limit exposure to Cr(VI) in
two chromate production plants in the United States and two plants in
Germany (Exs. 47-24-1; 47-27, pp. 15-16; 47-35-1, pp. 7-8). These
commenters suggested that OSHA should use these cohorts to model risk
of lung cancer from low exposures to Cr(VI). Unfortunately, the public
did not have a chance to comment on this study because documents
related to it were submitted to the docket after the time period when
new information should have been submitted. However, OSHA reviewed the
study and comments that were submitted to the docket. Based on the
information submitted, the Agency does not believe that quantitative
analysis of these studies would provide additional information on risk
from low exposures to Cr(VI).
    A cohort analysis based on the U.S. plants is presented in an April
2005 publication by Luippold et al. (Ex. 47-24-2). Luippold et al.
studied a total of 617 workers with at least one year of employment,
including 430 at a plant built in the early 1970s (``Plant 1'') and 187
hired after the 1980 institution of exposure-reducing process and work
practice changes in a second plant (``Plant 2''). Workers were followed
through 1998. Personal air-monitoring measures available from 1974 to
1988 for the first plant and from 1981 to 1998 for the second plant
indicated that exposure levels at both plants were low, with overall
geometric mean concentrations below 1.5 [mu]g/m3 and area-
specific average personal air sampling values not exceeding 10 [mu]g/
m3 for most years (Ex. 47-24-2, p. 383). By the end of
follow-up, which lasted an average of 20.1 years for workers at Plant 1
and 10.1 years at Plant 2, 27 cohort members (4%) were deceased. There
was a 41% deficit in all-cause mortality when compared to all-cause
mortality from age-specific state reference rates, suggesting a strong
healthy worker effect. Lung cancer was 16% lower than expected based on
three observed vs. 3.59 expected cases, also using age-specific state
reference rates (Ex. 47-24-2, p. 383). The authors concluded that
``[t]he absence of an elevated lung cancer risk may be a favorable
reflection of the postchange environment. However, longer follow-up
allowing an appropriate latency for the entire cohort will be needed to
confirm this conclusion'' (Ex. 47-24-2, p. 381).
    OSHA agrees with the study authors that the follow-up in this study
was not sufficiently long to allow potential Cr(VI)-related lung cancer
deaths to occur among many cohort members. The mean times since first
exposure of 10 and 20 years for Plant 1 and Plant 2 employees,
respectively, suggest that most workers in the cohort may not have
completed the `` * * * typical latency period of 20 years or more''
that Luippold et al. suggest is required for occupational lung cancer
to emerge (Ex. 47-24-2, p. 384). Other important limitations of this
study include the striking healthy worker effect on the SMR analysis,
and the relatively young age of most workers at the end of follow-up
(approximately 90% <  60 years old) (Ex. 47-24-2, p. 383). OSHA also
agrees with the study authors' statements that `` * * * the few lung
cancer deaths in this cohort precluded * * * [analyses to] evaluate
exposure-response relationships * * * '' (Ex. 47-24-2, p. 384).
    Although OSHA's model predicts high excess lung cancer risk for
highly exposed individuals (e.g., workers exposed for 45 years at the
previous PEL of 52 [mu]g/m3), the model would predict much
lower risks for workers with low exposures, as in the Luippold (2005)
cohorts. To provide a point of comparison between the results of the
Luippold et al. (2005) `post-change' study and OSHA's risk model, the
Agency used its risk model to generate an estimate of lung cancer risk
for a population with exposure characteristics approximately similar to
the `post-change' cohorts described in Luippold et al. (2005). It
should be noted that since this comparative analysis used year 2000
U.S. reference rates were rather than the state-, race-, and gender-
specific historical reference mortality rates used by Luippold et al.
(2005), this risk calculation provides only a rough estimate of
expected excess lung cancer risk for the cohort. The derivation of
OSHA's risk model (based on the preferred Gibb and Luippold

(2003) cohorts) is described in Sections VI.C.1 and VI.C.2.
    It is difficult to tell from the publication what the average level
or duration of exposure was for the cohort. However, personal sampling
data reported by Luippold et al. (2005) had annual geometric mean 8-
hour TWA concentrations ``much less'' than 1.5 [mu]g/m3 in
most years (Ex. 47-24-2, p. 383). Most workers also probably had less
than 20 years of exposure, given the average follow-up periods of 20
and 10 years reported for the Luippold (2005) Plant 1 and Plant 2,
respectively. OSHA assumed that workers had TWA exposures of 1.5 [mu]g/
m3 for 20 years, with the understanding that this assumption
would lead to somewhat higher estimates of risk than OSHA s model would
predict if the average exposure of the cohort was known. Using these
assumptions, OSHA's model predicts a 2-9% excess lung cancer risk due
to Cr(VI) exposure, or less than four cancers in the population the
size and age of the Luippold 2005 cohort.
    Since this analysis used year 2000 U.S. reference rates rather than
the state-, race-, and gender-specific historical reference mortality
rates used by Luippold et al. (2005), this risk calculation provides
only a rough estimate of the lung cancer risk that OSHA's model would
predict for the cohort. Nevertheless, it illustrates that for a
relatively young population with low exposures, OSHA's risk model
(derived from the preferred Gibb and Luippold 2003 cohorts) predicts
lung cancer risk similar to that observed in the low-exposure Luippold
2005 cohort. The small number of lung cancer deaths observed in
Luippold 2005 should not be considered inconsistent with the risk
estimates derived using models developed by OSHA based on the Gibb and
Luippold (2003) cohorts (Ex. 47-24-2, p. 383).
    Some commenters believed that analysis of the unpublished German
cohorts would demonstrate that lung cancer risk was only increased at
the highest Cr(VI) levels and, therefore, could form the basis for an
exposure threshold (Exs. 47-24-1; 47-35-1). Although no data were
provided to corroborate their comments, the Society of the Plastics
Industry requested that OSHA obtain and evaluate the German study as
``new and available evidence which may suggest a higher PEL than
proposed'' (Ex. 47-24-1, p. 4).
    Following the close of the comment period, OSHA gained access to a
2002 final contract report by Applied Epidemiology Inc. prepared for
the Industrial Health Foundation (Ex. 48-1-1; 48-1-2) and a 2005
prepublication by ENVIRON Germany (Ex. 48-4). The 2002 report contained
detailed cohort descriptions, exposure assessments, and mortality
analyses of `post-change' workers from the two German chromate
production plants referred to above and two U.S. chromate production
plants, one of which is plant 1 discussed in the 2005 study by Luippold
et al. The mortality and multivariate analyses were performed on a
single combined cohort from all four plants. The 2005 prepublication
contained a more abbreviated description and analysis of a smaller
cohort restricted to the two German plants only. The cohorts are
referred to as `post-change' because the study only selected workers
employed after the participating plants switched from a high-lime to a
no-lime (or very low lime facility, in the case of U.S. plant 1)
chromate production process and implemented industrial hygiene
improvements that considerably reduced Cr(VI) air levels in the
workplace.
    The German cohort consisted of 901 post-change male workers from
two chromate production plants employed for at least one year.
Mortality experience of the cohort was evaluated through 1998. The
study found elevated lung cancer mortality (SMR=1.48 95% CI: 0.93-2.25)
when compared to the age- and calendar year-adjusted German national
population rates (Ex. 48-4). The cohort lacked sufficient job history
information and air monitoring data to develop an adequate job-exposure
matrix required to estimate individual airborne exposures (Ex. 48-1-2).
Instead, the researchers used the large amount of urinary chromium data
from routine biomonitoring of plant employees to analyze lung cancer
mortality using cumulative urinary chromium as an exposure surrogate,
rather than the conventional cumulative Cr(VI) air concentrations. The
study reported a statistically significant two-fold excess lung cancer
mortality (SMR=2.09; 95% CI: 1.08-3.65; 12 observed lung cancer deaths)
among workers in the highest cumulative exposure grouping (i.e. >200
[mu]g Cr/L--yr). There was no increase in lung cancer mortality in the
lower exposure groups, but the number of lung cancer deaths was small
(i.e. < 5 deaths) and the confidence intervals were wide. Logistic
regression modeling in the multi-plant cohort (i.e. German and U.S.
plants combined) showed an increased risk of lung cancer in the high
(OR=20.2; 95% CI: 6.2-65.4; 10 observed deaths) and intermediate
(OR=4.9; 95% CI: 1.5-16.0; 9 deaths) cumulative exposure groups when
compared to the low exposure group (Ex. 48-1-2, Table 18). The lung
cancer risks remained unchanged when smoking status was controlled for
in the model, indicating that the elevated risks were unlikely to be
confounded by smoking in this study.
    OSHA does not believe that the results of the German study provide
a basis on which to establish a threshold exposure below which no lung
cancer risk exists. Like the U.S. post-change cohort (i.e., Luippold
(2005) cohort) discussed above, small cohort size, few lung cancer
cases (e.g., 10 deaths in the three lowest exposure groups combined)
and limited follow-up (average 17 years) severely limit the power to
detect small increases in risk that may be present with low cumulative
exposures. The limited power of the study is reflected in the wide
confidence intervals associated with the SMRs. For example, there is no
apparent evidence of excess lung cancer (SMR=0.95; 95% CI: 0.26-2.44)
in workers exposed to low cumulative urine chromium levels between 40-
100 [mu]g Cr/L--yr. However, the lack of precision in this estimate is
such that a two-fold increase in lung cancer mortality can not be ruled
out with a high degree of confidence. Although the study authors state
that the data suggest a possible threshold effect, they acknowledge
that ``demonstrating a clear (and statistically significant) threshold
response in epidemiological studies is difficult especially [where], as
in this study, the number of available cases is relatively small, and
the precise estimation of small risks requires large numbers'' (Ex. 48-
4, p. 8). OSHA agrees that the number of lung cancer cases in the study
is too small to clearly demonstrate a threshold response or precisely
estimate small risks.
    OSHA has relied upon a larger, more robust cohort study for its
risk assessment than the German cohort. In comparison, the Gibb cohort
has about five times the person-years of observation (70736 vs. 14684)
and number of lung cancer cases (122 vs. 22). The workers, on average,
were followed longer (30 vs. 17 years) and a greater proportion of the
cohort is deceased (36% vs. 14%). Limited air monitoring from the
German plants indicate that average plant-wide airborne Cr(VI) roughly
declined from about 35 [mu]g Cr(VI)/m\3\ in the mid 1970s to 5 [mu]g
Cr(VI)/m\3\ in the 1990s (2002 report; Ex. 7-91). This overlaps the
Cr(VI) air levels in the Baltimore plant studied by Gibb et al. (Ex.
47-8). Furthermore, cumulative exposure estimates for members of the
Gibb cohort were individually reconstructed

from job histories and Cr(VI) air monitoring data. These airborne
Cr(VI) exposures are better suited than urinary chromium for evaluating
occupational risk at the permissible exposure limits under
consideration by OSHA. An appropriate conversion procedure that
credibly predicts time-weighted average Cr(VI) air concentrations in
the workplace from urinary chromium measurements is not evident and,
thus, would undoubtedly generate additional uncertainty in the risk
estimates. For the above reasons, OSHA believes the Gibb cohort
provides a stronger dataset than the German cohort on which to assess
the existence of a threshold exposure. This and other issues pertaining
to the relationship between the cumulative exposure and lung cancer
risk are further discussed in section VI.G.1.a.

C. Quantitative Risk Assessments Based on the Gibb Cohort

    Quantitative risk assessments were performed on the exposure-
response data from the Gibb cohort by three groups: Environ
International (Exs. 33-15; 33-12) under contract with OSHA; the
National Institute for Occupational Safety and Health (Ex. 33-13); and
Exponent (Ex. 31-18-15-1) for the Chrome Coalition. All reported
similar risks for Cr(VI) exposure over a working lifetime despite using
somewhat different modeling approaches. The exposure-response data,
risk models, statistical evaluation, and risk estimates reported by
each group are discussed below.
1. Environ Risk Assessments
    In 2002, Environ International (Environ) prepared a quantitative
analysis of the association between Cr(VI) exposure and lung cancer
(Ex. 33-15) , which was described in detail in the Preamble to the
Proposed Rule (69 FR at 59364-59365). After the completion of the 2002
Environ analysis, individual data for the 2357 men in the Gibb et al.
cohort became available. The new data included cumulative Cr(VI)
exposure estimates, smoking information, date of birth, race, date of
hire, date of termination, cause of death, and date of the end of
follow-up for each individual (Ex. 35-295). The individual data allowed
Environ to do quantitative risk assessments based on (1) redefined
exposure categories, (2) alternate background reference rates for lung
cancer mortality, and (3) Cox proportional hazards modeling (Ex. 33-
12). These are discussed below and in the 2003 Environ analysis (Ex.
33-12).
    The 2003 Environ analysis presented two alternate groupings with
ten cumulative Cr(VI) exposure groups each, six more than reported by
Gibb et al. and used in the 2002 analysis. One alternative grouping was
designed to divide the person-years of follow-up fairly evenly across
groups. The other alternative allocated roughly the same number of
observed lung cancers to each group. These two alternatives were
designed to remedy the uneven distribution of observed and expected
cases in the Gibb et al. categories, which may have caused parameter
estimation problems due to the small number of cases in some groups.
The new groupings assigned adequate numbers of observed and expected
lung cancer cases to all groups and are presented in Table VI-1.
    Environ used a five-year lag to calculate cumulative exposure for
both groupings. This means that at any point in time after exposure
began, an individual's cumulative exposure would equal the product of
chromate concentration and duration of exposure, summed over all jobs
held up to five years prior to that point in time. An exposure lag is
commonly used in exposure-response analysis for lung cancer since there
is a long latency period between first exposure and the development of
disease. Gibb et al. found that models using five- and ten-year lags
provided better fit to the mortality data than lags of zero, two and
twenty years (Ex. 31-22-11).
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    The 2003 Environ analysis also derived expected cases using lung
cancer rates from alternative reference populations. In addition to the
State of Maryland lung cancer rates that were used by Gibb et al.,
Environ used age- and race-specific rates from the city of Baltimore,
where the plant was located. Baltimore may represent a more appropriate
reference population because most of the cohort members

resided in Baltimore and Baltimore residents may be more similar to the
cohort members than the Maryland or U.S. populations in their co-
exposures and lifestyle characteristics, especially smoking habits and
urban-related risk factors. On the other hand, Baltimore may not be the
more appropriate reference population if the higher lung cancer rates
in the Baltimore population primarily reflect extensive exposure to
industrial carcinogens. This could lead to underestimation of risk
attributable to Cr(VI) exposure.
    The 2003 analysis used two externally standardized models, a
relative risk model (model E1 below) and an additive risk model (model
E2) defined as follows:

E1. Ni = C0 * Ei * (1 +
C1Di + C2Di\2\)
E2. Ni = C0 * Ei + PYi *
(C1Di + C2Di\2\)

where Ni is the predicted number of lung cancers in the i
th group; PYi is the number of person-years for
group i; Ei is the expected number of lung cancers in that
group, based on the reference population; Di is the mean
cumulative dose for that group; and C0, C1, and
C2 are parameters to be estimated. Both models initially
included quadratic exposure terms (C2Di\2\ ) as
one way to test for nonlinearity in the exposure-response. Model E1 is
a relative risk model, whereas Model E2 is an additive risk model. In
the case of additive risk models, the exposure-related estimate of
excess risk is the same regardless of the age- and race-specific
background rate of lung cancer. For relative risk models, a dose term
is multiplied by the appropriate background rate of lung cancer to
derive an exposure-related estimate of risk, so that excess risk always
depends on the background.
    Maximum likelihood techniques were used to estimate the parameters
C0, C1, and C2. Likelihood ratio tests
were used to determine which of the model parameters contributed
significantly to the fit of the model. Parameters were sequentially
added to the model, starting with C1, when they contributed
significantly (p <  0.05) to improving the fit. Parameters that did not
contribute significantly, including the quadratic exposure terms
(C2Di\2\ ), were removed from the models.
    Two Cox proportional hazards models were also fit to the individual
exposure-response data. The model forms were:

C1. h(t;z;D) = h0(t)*exp([beta]1z +
[beta]2D)

C2. h(t;z;D) = h0(t)*[exp([beta]1z)][1 +
[beta]2D]

where h is the hazard function, which expresses the age-specific rate
of lung cancer among workers, as estimated by the model. In addition, t
is age, z is a vector of possible explanatory variables other than
cumulative dose, D is cumulative dose, h0(t) is the baseline
hazard function (a function of age only), [beta]2 is the
cumulative dose coefficient, and [beta]1 is a vector of
coefficients for other possible explanatory variables--here, cigarette
smoking status, race, and calendar year of death (Ex. 35-57). Cox
modeling is an approach that uses the experience of the cohort to
estimate an exposure-related effect, irrespective of an external
reference population or exposure categorization. Because they are
internally standardized, Cox models can sometimes eliminate concerns
about choosing an appropriate reference population and may be
advantageous when the characteristics of the cohort under study are not
well matched against reference populations for which age-related
background rates have been tabulated. Model C1 assumes the lung cancer
response is nonlinear with cumulative Cr(VI) exposure, whereas C2
assumes a linear lung cancer response with Cr(VI) exposure. For the Cox
proportional hazards models, C1 and C2, the other possible explanatory
variables considered were cigarette smoking status, race, and calendar
year of death.
    The externally standardized models E1 and E2 provided a good fit to
the data (p>=0.40). The choice of exposure grouping had little effect
on the parameter estimates of either model E1 or E2. However, the
choice of reference rates had some effect, notably on the
``background'' parameter, C0, which was included as a fitted
parameter in the models to adjust for differences in background lung
cancer rates between cohort members and the reference populations. For
example, values of C0 greater than one ``inflate'' the base
reference rates, reducing the magnitude of excess risks in the model.
Such an adjustment was necessary for the Maryland reference population
(the maximum likelihood estimate of C0 was significantly
higher than one), but not for the Baltimore city reference population
(C0 was not significantly different from one). This result
suggests that the Maryland lung cancer rates may be lower than the
cohort's background lung cancer rates, but the Baltimore city rates may
adequately reflect the cohort background rates. The inclusion of the
C0 parameter yielded a cumulative dose coefficient that
reflected the effect of exposure and not the effect of differences in
background rates, and was appropriate.
    The model results indicated a relatively consistent cumulative dose
coefficient, regardless of reference population. The coefficient for
cumulative dose in the models ranged from 2.87 to 3.48 per mg/m\3\-yr
for the relative risk model, E1, and from 0.0061 to 0.0071 per mg/m\3\-
person-yr for the additive risk model, E2. These coefficients determine
the slope of the linear cumulative Cr(VI) exposure-lung cancer response
relationship. In no case did a quadratic model fit the data better than
a linear model.
    Based on comparison of the models' AIC values, Environ indicated
that the linear relative risk model E1 was preferred over the additive
risk model E2. OSHA agrees with Environ's conclusion. The relative risk
model is also preferred over an additive risk model because the
background rate of lung cancer varies with age. It may not be
appropriate to assume, as an additive model does, that increased lung
cancer risk at age 25, where background risk is relatively low, would
be the same (for the same cumulative dose) as at age 65, where
background rates are much higher.
    The Cox proportional hazards models, C1 and C2, also fit the data
well (although the fit was slightly better for model C2 than C1).
Recall that for the Cox proportional hazards models, C1 and C2, the
other possible explanatory variables considered were cigarette smoking
status, race, and calendar year of death. For both models, addition of
a term for smoking status significantly improved the fit of the models
to the data (p< 0.00001). The experience with model C1 indicated that
race (p=0.15) and year of death (p=0.4) were not significant
contributors when cumulative dose and smoking status were included in
the model. Based on results for model C1, race and year of death were
not considered by Environ in the linear model C2. The cumulative dose
coefficient, [beta]2, was 1.00 for model C1 and 2.68 for
model C2. A more complete description of the models and variables can
be found in the 2003 Environ analysis (Ex. 33-12, p. 10).
    Lifetable calculations were made of the number of extra lung
cancers per 1000 workers exposed to Cr(VI) based on models E1, E2, C1,
and C2, assuming a constant exposure from age 20 through a maximum of
age 65. The lifetable accounted for both lung cancer risk and competing
mortality through age 100. Rates of lung cancer and other mortality for
the lifetable calculations were based, respectively, on 2000 U.S. lung
cancer and all-cause mortality rates for both sexes and all races. In
addition to the maximum likelihood estimates, 95% confidence intervals
for the excess lifetime risk were derived. Details about the procedures
used to estimate parameters, model fit, lifetable calculations, and
confidence intervals

are described in the 2003 Environ report (Ex. 33-12, p. 8-9).
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    Table VI-2 shows each model's predictions of excess lifetime lung
cancer risk from a working lifetime of exposure to various Cr(VI) air
levels. The estimates are very consistent regardless of model, exposure
grouping, or reference population. The model that appears to generate
results least similar to the others is C1, which yielded one of the
higher risk estimates at 52 [mu]g/m3, but estimated the
lowest risks for exposure levels of 10 [mu]g/m3 or lower.
The change in magnitude, relative to the other models, is a result of
the nonlinearity of this model. Confidence limits for all models,
including C1, tend to overlap, suggesting a fair degree of statistical
consistency.
2. National Institute for Occupational Safety and Health (NIOSH) Risk
Assessment
    NIOSH (Ex. 33-13) developed a risk assessment from the Gibb cohort.
The NIOSH analysis, like the 2003 Environ assessment, used the cohort
individual data files to compute cumulative Cr(VI) exposure. However,
NIOSH also explored some other exposure-related assumptions. For
example, they performed the dose-response analysis with lag times in
addition to the 5-year lag used by Environ. NIOSH also analyzed dose-
response using as many as 50 exposure categories, although their report
presents data in five cumulative Cr(VI) exposure groupings.
    NIOSH incorporated information on the cohort smoking behavior in
their quantitative assessments. They estimated (packs/day)-years of
cumulative smoking for each individual in the cohort, using information
from a questionnaire that was administered at the time of each cohort
member's date of hire. To estimate cumulative smoking, NIOSH assumed
that the cohort members maintained the level of smoking reported in the
questionnaire from the age of 18 through the end of follow-up.
Individuals with unknown smoking status were assigned a value equal to
the average smoking level among all individuals with known smoking
levels (presumably including non-smokers). Individuals who were known
to smoke but for whom the amount was unknown were assigned a smoking
level equal to the average of all smokers.
    NIOSH considered six different relative risk models, fit to the
Gibb cohort data by Poisson regression methods. They did not consider
additive risk models. The six relative risk models were externally
standardized using age- and race-specific U.S. lung cancer rates. Their
background coefficients, C0, explicitly included smoking,
race, and age terms to adjust for differences between the cohort and
the reference population. These models are described as follows:

NIOSH1a: Ni = C0 * Ei *
exp(C1Di)
NIOSH1b: Ni = C0 * Ei *
exp(C1Di\1/2\\)
NIOSH1c: Ni = C0 * Ei * exp(1 +
C1Di + C2Di2)
NIOSH1d: Ni = C0 * Ei * (1 +
Di)[alpha]
NIOSH1e: Ni = C0 * Ei * (1 +
C1Di)
NIOSH1f: Ni = C0 * Ei * (1 +
C1Di[alpha])

where the form of the equation has been modified to match the format
used in the Environ reports. In addition, NIOSH fit Cox proportional
hazard models (not presented) to the lung cancer mortality data using
the individual cumulative Cr(VI) exposure estimates.
    NIOSH reported that the linear relative risk model 1e generally
provided a superior fit to the exposure-response data when compared to
the various log linear models, 1a-d. Allowing some non-linearity (e.g.,
model 1f) did not significantly improve the goodness-of-fit, therefore,
they considered the linear relative risk model form 1e (analogous to
the Environ model E1) to be the most appropriate for determining their
lifetime risk calculations. A similar fit could be achieved with a log-
linear power model (model 1d) using log-transformed cumulative Cr(VI)
and a piece-wise linear specification for the cumulative smoking term.
    The dose coefficient (C1) for the linear relative risk
model 1e was estimated by NIOSH to be 1.444 per [mu]g CrO3/
m3-yr (Ex. 33-13, Table 4). If the exposures were converted
to units of [mu]g Cr(VI)/m3-yr, the estimated cumulative
dose coefficient would be 2.78 (95% CI: 1.04 to 5.44) per [mu]g/
m3-yr. This value is very close to the estimates derived in
the Environ 2003 analysis (maximum likelihood estimates ranging from
2.87 to 3.48 for model E1, depending on the exposure grouping and the
reference population). Lifetime risk estimates based on the NIOSH-
estimated dose coefficient and the Environ lifetable method using 2000
U.S. rates for lung cancer and all cause mortality are shown in Table
VI-3. The values are very similar to the estimates predicted by the
Environ 2003 analysis (Table VI-3). The small difference may be due to
the NIOSH adjustment for smoking in the background coefficient. NIOSH
found that excess lifetime risks for a 45-year occupational exposure to
Cr(VI) predicted by the best-fitting power model gave very similar
risks to the preferred linear relative risk model at TWA Cr(VI)
concentrations between 0.52 and 52 [mu]g/m3 (Ex. 33-13,
Table 5). Although NIOSH did not report the results, they stated that
Cox modeling produced risk estimates similar to the Poisson regression.
The consistency between Cox and Poisson regression modeling is
discussed further in section VI.C.4.
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    NIOSH reported a significantly higher dose-response coefficient for
nonwhite workers than for white workers. That is, nonwhite workers in
the Gibb cohort are estimated to have a higher excess risk of lung
cancer than white workers, given equal cumulative exposure to Cr(VI).
In contrast, no significant race difference was found in the Cox
proportional hazards analysis reported by 2003 Environ.

3. Exponent Risk Assessment
    In response to OSHA's Request For Information, Exponent prepared an
analysis of lung cancer mortality from the Gibb cohort. Like the 2003
Environ and NIOSH analyses, the Exponent analysis relied on the
individual worker data. Exponent performed their dose-response analyses
based on three different sets of exposure categories using two
reference populations and 70,808 person-years of follow-up. A total of
four analyses were completed, using (1) Maryland reference rates and
the four Gibb et al. exposure categories; (2) Baltimore reference rates
and the four Gibb et al. exposure categories; (3) Baltimore reference
rates and six exposure groups defined by Exponent; and (4) Baltimore
City reference rates and five exposure categories, obtained by removing
the highest of the six groups defined by Exponent from the dose-
response analysis. A linear relative risk model without a background
correction term (the term C0 used by Environ and NIOSH) was
applied in all of these cases and cumulative exposures were lagged five
years (as done by Environ and NIOSH). The analyses showed excess
lifetime risk between 6 and 14 per 1000 for workers exposed to 1 [mu]g/
m\3\ Cr(VI) for 45 years.
    The analysis using Maryland reference lung cancer rates and the
Gibb et al. four-category exposure grouping yielded an excess lifetime
risk of 14 per 1000. This risk, which is higher than the excess
lifetime risk estimates by Environ and NIOSH for the same occupational
exposure, probably results from the absence of a background rate
coefficient (C0) in Exponent's model. As reported in the
Environ 2002 and 2003 analyses, the Maryland reference lung cancer
rates require a background rate coefficient greater than 1 to achieve
the best fit to the exposure-response data. The unadjusted Maryland
rates probably underestimate the cohort's background lung cancer rate,
leading to overestimation of the risk attributable to cumulative Cr(VI)
exposure.
    The two analyses that used Baltimore reference rates and either
Exponent's six-category exposure grouping or the Gibb et al. four-
category grouping both resulted in an excess lifetime unit risk of 9
per 1000 for workers exposed to 1 [mu]g/m\3\ Cr(VI) for 45 years (Ex.
31-18-15-1, p. 41). This risk is close to estimates reported by Environ
using their relative risk model (E1) and Baltimore reference rates for
the same occupational exposure (Table VI-2). The Environ analysis
showed that, unlike the Maryland-standardized model discussed above,
the Baltimore-standardized models had background rate coefficients very
close to 1, the ``default'' value assumed by the Exponent relative risk
model. This suggests that the Baltimore reference rates may represent
the background lung cancer rate for this cohort more accurately than
the Maryland reference rates.
    The lowest excess lifetime unit risk for workers exposed to 1
[mu]g/m\3\ Cr(VI) for 45 years reported by Exponent, at 6 per 1000, was
derived from the analysis that excluded the highest of Exponent's six
exposure groups. While this risk value is close to the Environ and
NIOSH unit risk estimates, the analysis merits some concern. Exponent
eliminated the highest exposure group on the basis that most cumulative
exposures in this group were higher than exposures usually found in
current workplace conditions. However, eliminating this group could
exclude possible long-term exposures (e.g., >15 years) below the
previous OSHA PEL (52 [mu]g/m\3\ ) from the risk analysis. Moreover, no
matter what current exposures might be, data on higher cumulative
exposures are relevant for understanding the dose-response
relationships.
    In addition, the Exponent six category cumulative exposure grouping
may have led to an underestimate of the dose effect. The definition of
Exponent's six exposure groups was not related to the distribution of
cumulative exposure associated with individual person-years, but rather
to the distribution of cumulative exposure among the workers at the end
of their employment. This division does not result in either a uniform
distribution of person-years or observed lung cancer cases among
exposure categories. In fact, the six category exposure groupings of
both person-years and observed lung cancers were very uneven, with a
preponderance of both allocated to the lowest exposure group. This
skewed distribution of person-years and observed cases puts most of the
power for detecting significant differences from background cancer
rates at low exposure levels, where these differences are expected to
be small, and reduces the power to detect any significant differences
from background at higher exposure concentrations.
4. Summary of Risk Assessments Based on the Gibb Cohort
    OSHA finds remarkable consistency among the risk estimates from the
various quantitative analyses of the Gibb cohort. Both Environ and
NIOSH determined that linear relative risk models generally provided a
superior fit to the data when compared to other relative risk models,
although the confidence intervals in the non-linear Cox model reported
by Environ overlapped with the confidence intervals in their linear
models. The Environ 2003 analysis further suggested that a linear
additive risk model could adequately describe the observed dose-
response data. The risk estimates for NIOSH and Environ's best-fitting
models were statistically consistent (compare Tables VI-2 and VI-3).
    The choice of reference population had little impact on the risk
estimates. NIOSH used the entire U.S. population as the reference, but
included adjustment terms for smoking, age and race in its models. The
Environ 2003 analysis used both Maryland and Baltimore reference lung
cancer rates, and included a generic background coefficient
C0 to adjust for potential differences in background risk
between the reference population and the worker cohort. This term was
significant in the fitted model when Maryland rates were used for
external standardization, but not when Baltimore rates were used. Since
no adjustment in the model background term was required to better fit
the exposure-response data using Baltimore City lung cancer rates, they
may best represent the cohort's true background lung cancer incidence.
OSHA considers the inclusion of such adjustment factors, whether
specific to smoking, race, and age (as defined by NIOSH), or generic
(as defined by Environ), to be appropriate and believes they contribute
to accurate risk estimation by helping to correct for confounding risk
factors. The Cox proportional hazard models, especially the linear Cox
model, yielded risk estimates that were generally consistent with the
externally standardized models.
    Finally, the number of exposure categories used in the analysis had
little impact on the risk estimates. When an appropriate adjustment to
the background rates was included, the four exposure groups originally
defined by Gibb et al. and analyzed in the 2002 Environ report, the six
exposure groups defined by Exponent, the two alternate sets of ten
exposure categories as defined in the 2003 Environ analysis, and the
fifty groups defined and aggregated by NIOSH all gave essentially the
same risk estimates. The robustness of the results to various
categorizations of cumulative exposure adds credence to the risk
projections.
    Having reviewed the analyses described in this section, OSHA finds
that the best estimates of excess lung cancer risk to workers exposed
to the previous PEL (52 [mu]g Cr(VI)/m3) for a

working lifetime are about 300 to 400 per thousand based on data from
the Gibb cohort. The best estimates of excess lung cancer risks to
workers exposed to other TWA exposure concentrations are presented in
Table VI-2. These estimates are consistent with predictions from
Environ, NIOSH and Exponent models that applied linear relative and
additive risk models based on the full range of cumulative Cr(VI)
exposures experienced by the Gibb cohort and used appropriate
adjustment terms for the background lung cancer mortality rates.

D. Quantitative Risk Assessments Based on the Luippold Cohort

    As discussed earlier, Luippold et al. (Exs. 35-204; 33-10) provided
information about the cohort of workers employed in a chromate
production plant in Painesville, Ohio. Follow-up for the 482 members of
the Luippold cohort started in 1940 and lasted through 1997, with
accumulation of person-years for any individual starting one year after
the beginning of his first exposure. There were 14,048 total person-
years of follow-up for the cohort. The person-years were then divided
into five exposure groups that had approximately equal numbers of
expected lung cancers in each group. Ohio reference rates were used to
compute expected numbers of deaths. White male rates were used because
the number of women was small (4 out of 482) and race was known to be
white for 241 of 257 members of the cohort who died and for whom death
certificates were available. The 1960-64 Ohio rates (the earliest
available) were assumed to hold for the time period from 1940 to 1960.
Rates from 1990-94 were assumed to hold for the period after 1994. For
years between 1960 and 1990, rates from the corresponding five-year
summary were used. There were significant trends for lung cancer SMR as
a function of year of hire, duration of employment, and cumulative
Cr(VI) exposure. The cohort had a significantly increased SMR for lung
cancer deaths of 241 (95% C.I. 180 to 317).
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    Environ conducted a risk assessment based on the cumulative Cr(VI)
exposure-lung cancer mortality data from Luippold et al. and presented
in Table VI-4 (Ex. 33-15). Cumulative Cr(VI) exposures were categorized
into five groups with about four expected lung cancer deaths in each
group. In the absence of information to the contrary, Environ assumed
Luippold et al. did not employ any lag time in determining the
cumulative exposures. The calculated

and expected numbers of lung cancers were derived from Ohio reference
rates. Environ applied the relative and additive risk models, E1 and
E2, to the data in Table VI-4.
    Linear relative and additive risk models fit the Luippold cohort
data adequately (p>=0.25). The final models did not include the
quadratic exposure coefficient, C2, or the background rate
parameter, C0, as they did not significantly improve the fit
of the models. The maximum likelihood estimates for the Cr(VI)
exposure-related parameter, C1, of the linear relative and
additive risk models were 0.88 per mg/m3-yr and 0.0014 per
mg/m3-person-yr, respectively. The C1 estimates
based on the Luippold cohort data were about 2.5-fold lower than the
parameter estimates based on the Gibb cohort data. The excess lifetime
risk estimate calculated by Environ for a 45-year working-lifetime
exposure to 1 [mu]g Cr(VI)/m3 (e.g., the unit risk) for both
models was 2.2 per 1000 workers (95% confidence intervals from 1.3 to
3.5 per 1000 for the relative risk model and 1.2 to 3.4 per 1000 for
the additive risk model) using a lifetable analysis with 1998 U.S.
mortality reference rates. These risks were 2.5 to 3-fold lower than
the projected unit risks based on the Gibb data set for equivalent
cumulative Cr(VI) exposures.
    Crump et al. (Exs. 33-15; 35-58; 31-18) also performed an exposure-
response analysis from the Painesville data. In a Poisson regression
analysis, cumulative exposures were grouped into ten exposure
categories with approximately two expected lung cancer deaths in each
group. The observed and expected lung cancer deaths by Cr(VI) exposure
category are shown in Table VI-5. Ohio reference rates were used in
calculating the expected lung cancer deaths and cumulative exposures
were lagged five years.
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    The Crump et al. analysis used the same linear relative risk and
additive risk models as Environ on the individual data categorized into
the ten cumulative exposure groups (Ex. 35-58). Tests for systematic
departure from

linearity were non-significant for both models (p>=0.11). The
cumulative dose coefficient determined by the maximum likelihood method
was 0.79 (95% CI: 0.47 to 1.19) per mg/m3-yr for the
relative risk model and 0.0016 (95% CI: 0.00098 to 0.0024) per mg/
m3-person-yr for the additive risk model, respectively. The
authors noted that application of the linear models to five and seven
exposure groups resulted in no significant difference in dose
coefficients, although the results were not presented. The exposure
coefficients reported by Crump et al. were very similar to those
obtained by Environ above, although different exposure groups were used
and Crump et al. used a five-year lag for the cumulative exposure
calculation. The authors noted that the linear models did not fit the
exposure data grouped into ten categories very well (goodness-of-fit
p< =0.01) but fit the data much better with seven exposure groups
(p>0.3), replacing the many lower exposure categories where there were
few observed and expected cancers with more stable exposure groupings
with greater numbers of cancers. The reduction in number of exposure
groups did not substantially change the fitted exposure coefficients.
    The maximum likelihood estimate for the cumulative exposure
coefficient using the linear Cox regression model C2 was 0.66 (90% CI:
0.11 to 1.21), which was similar to the linear [Poisson regression]
relative risk model. When the Cox analysis was restricted to the 197
workers with known smoking status and a smoking variable in the model,
the dose coefficient for Cr(VI) was nearly identical to the estimate
without controlling for smoking. This led the authors to conclude that
``the available smoking data did not suggest that exposure to Cr(VI)
was confounded with smoking in this cohort, or that failure to control
for smoking had an appreciable effect upon the estimated carcinogenic
potency of Cr(VI)'' (Ex. 35-58, p. 1156).
    Given the similarity in results, OSHA believes it is reasonable to
use the exposure coefficients reported by Crump et al. based on their
groupings of the individual cumulative exposure data to estimate excess
lifetime risk from the Luippold cohort. Table VI-6 presents the excess
risk for a working lifetime exposure to various TWA Cr(VI) levels as
predicted by Crump et al.'s relative and additive risk models using a
lifetable analysis with 2000 U.S. rates for all causes and lung cancer
mortality. The resulting maximum likelihood estimates indicate that
working lifetime exposures to the previous Cr(VI) PEL would result in
excess lifetime lung cancer risks around 100 per 1000 (95% C.I. approx.
60-150). The risk estimates based on the Luippold cohort are lower than
the risk estimates based on the Gibb cohort, as discussed further in
section VI.F.
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E. Quantitative Risk Assessments Based on the Mancuso, Hayes, Gerin,
and Alexander Cohorts

    In addition to the preferred data sets analyzed above, there are
four other cohorts with available data sets for estimation of
additional lifetime risk of lung cancer. These are the Mancuso cohort,
the Hayes cohort, the Gerin cohort, and the Alexander cohort. Environ
did exposure-response analysis for all but the Hayes cohort (Ex. 33-
15). Several years earlier, the K.S. Crump Division did quantitative
assessments on data from the Mancuso and Hayes cohort, under contract
with OSHA (Ex.13-5). The U.S. EPA developed quantitative risk
assessments from the Mancuso cohort data for its Integrated Risk
Information System (Exs. 19-1; 35-52). The California EPA (Ex. 35-54),
Public Citizen Health Research Group (Ex. 1), and the U.S. Air Force
Armstrong Laboratory (AFAL) for the Department of Defense (Ex. 35-51)
performed assessments from the Mancuso data using the 1984 U.S. EPA
risk estimates as their starting point. The U.S. EPA also published a
risk assessment based on the Hayes cohort data (Ex. 7-102). Until the
cohort studies of Gibb et al. and Luippold et al. became available,
these earlier assessments provided the most current projected cancer
risks from airborne exposure to Cr(VI). The previous risk assessments
were extensively described in the NPRM sections VI.E.1 and VI.E.2 (69
FR at 59375-59378). While the risk estimates from Mancuso, Hayes,
Gerin, and Alexander data sets are associated with a greater degree of
uncertainty, it is nevertheless valuable to compare them to the risk
estimates from the higher quality Gibb and Luippold data sets in order
to determine if serious discrepancies exist between them. OSHA believes
evaluating consistency in risk among several worker cohorts adds to the
overall quality of the assessment.
    The Mancuso and Luippold cohorts each worked at the Painesville
plant but the worker populations did not overlap due to different
selection criteria. Exposure estimates were also based on different
industrial hygiene surveys. The Hayes and Gibb cohorts both worked at
the Baltimore plant. Even though Cr(VI) exposures were reconstructed
from monitoring data measured at different facilities resulting in
significantly different exposure-response functions (see section VI.F),
there was some overlap in the two study populations. As a result, the
projected risks from these data sets can not strictly be viewed as
independent estimates. The Gerin and Alexander cohorts were not
chromate production workers and are completely independent from the
Gibb and Luippold data sets. The quantitative assessment of the four
data sets and comparison with the risk assessments based on the Gibb
and Luippold cohorts are discussed below.
1. Mancuso Cohort
    As described in subsection VII.B.3, the Mancuso cohort was
initially defined in 1975 and updated in 1997. The cohort members were
hired between 1931 and 1937 and worked at the same Painesville facility
as the Luippold cohort workers. However, there was no overlap between
the two cohorts since all Luippold cohort workers were hired after
1939. The quantitative risk assessment by Environ used data reported in
the 1997 update (Ex. 23, Table XII) in which lung cancer deaths and
person-years of follow-up were classified into four groups of
cumulative exposure to soluble chromium, assumed to represent Cr(VI)
(Ex. 33-15). The mortality data and person-years were further broken
down by age of death in five year increments starting with age interval
40 to 44 years and going up to >75 years. No expected numbers of lung
cancers were computed, either for the cohort as a whole or for specific
groups of person-years. Environ applied an indirect method based on the
recorded median age and year of entry into the cohort to estimate age
information necessary to derive expected numbers of age- and calendar
year-adjusted lung cancers deaths required to complete the risk
assessment.
    Observed and expected lung cancer deaths by age and cumulative
exposure (mg/m\3\-yr) are presented in Table 3 of the 2002 Environ
report (Ex. 33-15, p. 39). The mean cumulative exposures to soluble
Cr(VI) were assumed to be equal to the midpoints of the tabulated
ranges. No lag was used for calculating the cumulative exposures.
Environ applied externally standardized risk models to these data,
similar to those described in section VI.C.1 but using an age-related
parameter, as discussed in the 2002 report (Ex. 33-15, p. 39). The
externally-standardized linear relative risk model with an age-