at the time the research was conducted. 14 15 b) There was no clear and convincing evidence that the research was fundamentally 16 unethical intended to seriously harm participants or that informed consent was not obtained. 17 18 c) There was no clear and convincing evidence of significant deficiencies in the ethical 19 procedures that could have resulted in serious harm ( based on the knowledge available at the 20 time the study was conducted) nor that information provided to participants seriously impaired 21 their informed consent. 22 23 The Board determined that there was not clear and convincing evidence that references to 24 the test material as a drug and other statements that could indicate the study constituted medical 25 research, that appear in the materials used to obtain informed consent should be considered 26 significantly deficient relative to the ethical standards prevailing when the study was conducted. 27 These statements are highly undesirable, and should not be used as part of modern day practice 28 in writing such consent materials. Nonetheless, it was unfortunately not uncommon for such 29 wording to have been used in consent materials in the past. In addition, other wording in the 30 consent materials clearly advised subjects that this was a study involving consuming an 31 insecticide. The Board, however, specifically rejects the arguments of the study sponsor that it 32 was appropriate to use the " drug" terminology because the consent materials were generic 33 materials used for a variety of studies. It also rejects the study sponsor's argument that because 34 the test material is sometimes used as a drug, it was appropriate to use that terminology in this 35 study even though this study in no way related to its use as a drug. 36 37 For the reasons discussed above, the Board determined that there was not clear and 38 convincing evidence that the administration of the test material for three additional days without 39 monitoring subjects' cholinesterase levels following the detection of cholinesterase inhibition 40 greater than 20 % in some subjects could have led to serious harm. There the study should not be 41 considered significantly deficient relative to the ethical standards prevailing when the study was 42 conducted. 43 44 ( 3) For the reasons discussed above, the Board determined that there was not clear and 45 convincing evidence that following the termination of dosing, the lack of medical surveillance to 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 47 of 69 establish the subjects' cholinesterase levels returned to normal could have led to serious harm. 1 Therefore the study should not be considered significantly deficient relative to the ethical 2 standards prevailing when the study was conducted. 3 4 The Board concluded that the Agency can rely on the results of this study, as appropriate 5 under current pesticide laws, given the absence of clear and convincing evidence that the 6 research was fundamentally unethical or significantly deficient relative to the ethical standards 7 prevailing when the study was conducted. 8 9 6. Ethephon 10 11 Charge to the Board 12 13 Ethephon is an organophosphorus compound that, upon absorption into plants, forms 14 ethylene gas which is an important component of the plant hormone complex. The Agency is 15 conducting an aggregate ( single chemical, multi route) risk assessment of ethephon. 16 17 Scientific consideration 18 19 The Agency's WOE document and DERs for ethephon describe the study design and 20 results of the ethephon repeat dose, oral, human toxicity studies. The WOE document also 21 discusses the Agency's conclusions regarding the usefulness of the human studies in the 22 aggregate, single chemical risk assessment. The Agency has concluded that the 28 day human 23 study is sufficiently robust to establish a point of departure for extrapolating acute and chronic 24 dietary risk. 25 26 Please comment on the scientific evidence that supports this conclusion. 27 28 Board Response to the Charge 29 30 Brief Overview of the Study 31 32 According to the Agency's weight of evidence document ( WOE) ( Kent 2006) , 33 " ethephon is an organophosphorus compound that, upon absorption into plants, forms ethylene 34 gas which is an important component of the plant hormone complex. The production of ethylene 35 by plants occurs naturally as crops mature but it can be slow during periods of unfavorable 36 weather. Ethylene generated from ethephon is absorbed by the plant tissues and moderates the 37 growth process. It is not similar in structure to other organophosphate pesticides. Ethephon 38 registrants have submitted many toxicity studies to support the continued pesticidal use of the 39 chemical, and among these studies are two involving direct dosing of human subjects that OPP is 40 considering using to establish endpoints to assess risk from exposure to ethephon. The WOE 41 document compares the strengths and weaknesses of the human and animal toxicity studies and 42 discusses how the human studies fit in with the animal studies, i. e., are the human data consistent 43 with animal data in terms of types of effects and effect levels or are there notable differences 44 between animals and humans." 45 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 48 of 69 According to the WOE document, " as a strong acid, ethephon is corrosive to the skin and 1 eyes ( Category I). In acute and subchronic neurotoxicity studies in rats, there were signs of 2 neurotoxicity at doses of 500 mg/ kg and above ( acute) and 300 mg/ kg ( subchronic). In dogs 3 there were no clinical signs of neurotoxicity evident at 75 mg/ kg/ day although plasma and RBC 4 cholinesterase were inhibited in animals at doses as low as 7.5 mg/ kg/ day." 5 6 There are two human studies under consideration, both involve direct dosing of human 7 subjects and are repeated dose oral studies, one for 28 days duration ( Reese 1972) and the other 8 for 16 days ( Weir 1977). 9 10 28 Day Oral Toxicity Study 11 12 In a non guideline oral toxicity human study ( Reese 1972), ethephon was administered 13 by capsule in a powdered formulation ( 10% a. i. weight/ weight) of hydrated silica and starch to 14 human adults ( 5/ sex) at an average dose of 1.8 mg a. i./ kg/ day or placebo 0 mg/ kg/ day ( 3/ sex) for 15 28 consecutive days. Administration of the test material or the placebo was given orally by 16 capsule divided into three daily doses. Each subject received 2 capsules postprandially for the 17 first two dosing periods; the third dose was given at the end of the work day in order to simulate 18 as closely as possible ingestion of the material as a crop residue. The capsules were dispensed 19 daily ( 5 days/ week) by an assistant who observed the subjects while they took each capsule and 20 recorded solicited comments related to the ingestion of the material during the first 8 hours. The 21 subjects and the assistant did not know which capsules were placebo or the test material. Each 22 Friday, the subjects received a supply of capsules to be taken during the two day weekend. All 23 subjects were monitored regularly for adverse effects. Hematology measurements, clinical 24 chemistry and urinalysis were conducted initially and on Days 7, 14, 21, 28 and 2 weeks 25 following the last administration. ChE ( plasma and RBC) determinations were conducted using 26 the   pH/ hr method ( modified Michel method) initially, and on Days 1, 2, 7, 14, 28 and 2 weeks 27 after the last administration. 28 29 Critique of 28 Day Oral Toxicity Study MRID 00036510 30 31 The ethephon subjects, though exhibiting normal physical appearance and behavior, 32 developed symptoms of diarrhea and increased urination and bowel movement. Three females 33 and one male experienced a sudden onset of diarrhea or an urgency of bowel movement of 1 4 34 days duration during the first week of the compound administration; the one male also 35 experienced loose stools for 2 weeks. Another male complained of stomach cramps or gas for 36 the duration of the study. One subject in the ethephon group was aymptomatic. Five subjects 37 experienced increased urgency and frequency of urination, 4 of whom experienced this symptom 38 throughout the study. Two subjects experienced decreased appetite while a third ( with diarrhea) 39 experienced increased appetite during the first 2 days of the study. It was stated that the 40 symptoms were " consistent with exposure to a cholinesterase inhibitor." The WOE document 41 stated " the clinical signs observed in the study, diarrhea and increased frequency of urination, are 42 consistent with a cholinergic mode of toxicity, but other signs associated with a cholinesterase 43 inhibitor such as pinpoint pupils ( miosis), sweating, runny nose, tearing, salivation, respiratory 44 distress and muscle fasciculation ( twitching), were not seen [ sic]; [ and] the test subjects reported 45 symptoms as they considered appropriate, and it is difficult to interpret what the self reported 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 49 of 69 symptoms mean in terms of a biological response." In fact, it is unknown if symptoms or signs 1 associated with a cholinesterase inhibitor were seen; they may not have been monitored or 2 specific requests for their reported made by the investigators. However, these symptoms, 3 probably related to irritant effects, are important results. 4 5 The Agency's Data Evaluation Record ( Khasawinah) and the WOE documents both 6 stated " None of the placebo subjects had similar complaints." This is probably not correct since 7 according to the investigators at least two of these controls were symptomatic as well some test 8 and control subjects also exhibited some atypical lymphocytes of unknown origin. 9 10 The WOE document states " Unexpectedly, plasma and RBC ChE activities were similar 11 or slightly higher than initial values in the test subjects. ([ The] details of the ChE determinations 12 were not provided.)" However, the ChE levels were not related to the diarrhea occurring in the 13 subjects upon examination of the time of symptom occurrence and ChE data provided. The 14 WOE document states " No compound effects regarding hematology, clinical chemistries and 15 urinalysis were reported", except the atypical lymphocytes of some. 16 17 It was concluded by the investigators of this study that the daily dose of 1.8 mg/ kg/ day is 18 the LOAEL for the oral ingestion of ethephon in human subjects. However, that is quite 19 uncertain since lower doses were not given. 20 21 16 Day Oral Toxicity Study 22 23 In the other non guideline oral toxicity human study ( Weir 1977), ethephon was 24 administered by capsule in a powdered formulation ( 2.5% a. i. weight/ weight) of hydrated silica 25 and starch to human adults ( 10/ sex) at an average dose of 0.5 mg a. i./ kg/ day or placebo 0 26 mg/ kg/ day ( 6 males and 4 females) for 16 consecutive days followed by a 29 day recovery 27 period ( phase three). The dosing phase ( phase two) was preceded with a 6 day period ( phase 28 one) where all subjects received daily placebos. Administration of the test material or the 29 placebo was given orally by capsule divided into three daily doses. Each subject received two 30 capsules postprandially for the first two dosing periods; the third dose was given at the end of the 31 work day in order to simulate as closely as possible ingestion of the material as a crop residue. 32 The capsules were dispensed daily ( 5 days/ week) by an assistant who observed the subjects 33 while they took each capsule and recorded solicited comments related to the ingestion of the 34 material for 8 hours. The subjects and the assistant did not know which capsules were placebo or 35 the test material in of the study phases. Each Friday, the subjects received a supply of capsules 36 to be taken during the two day weekend. All subjects were monitored regularly for adverse 37 effects. Hematology measurements and clinical chemistry were conducted on blood samples 38 collected during phases I, II and III while urinalysis was conducted on samples collected during 39 phase II. ChE ( plasma and RBC) determinations were conducted using the   pH/ hr method 40 ( modified Michel method) on blood collected during phases I, II, and III. 41 42 Critique of 16 day Oral Toxicity Study 43 44 No clinical symptoms were reported, but it is not known if this was an omission as the 45 report does not state that there were no symptoms or signs. Hematological, clinical chemistry 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 50 of 69 values and urinalysis parameters were comparable to the placebo controls. The updated 1 executive summary of the Agency Data Evaluation Record ( Khasawinah) for the 16 day human 2 study stated: " Plasma and RBC ChE activities were significantly inhibited in both placebo and 3 test groups. Therefore, this finding makes any conclusions regarding the effects attributable to 4 ethephon administration impossible. This is in contradiction to the study authors overall 5 conclusion that a daily ethephon oral dosage of 0.5 mg/ kg/ day produces significant plasma ChE 6 inhibition, which is reversible in 15 days." The study report states " Plasma cholinesterase was 7 significantly inhibited for the placebo group at 4, 8, 12, and 16 days during the dosage period. In 8 the test group, plasma cholinesterase was also depressed ( greater than the placebo group) at 4, 8, 9 12, and 16 days during the dosage period. Recovery does occur as indicated by the 15 and 29 10 post dosage values. RBC cholinesterase inhibition was similar for both placebo and test groups 11 ( slightly depressed in both groups) on days 4, 12, and 16 of the dosage period and day 15 of the 12 recovery period." Investigators also say that the test group plasma values were significantly 13 different than the placebo group values. 14 15 It appears that either the method of testing cholinesterase was poor, or, less likely, 16 something else was depressing plasma cholinesterase in this latter study while increasing it in the 17 former study. Possibly, as the ethephon risk assessment team concluded, measures of blood 18 cholinesterase, either plasma or RBC, were not appropriate for endpoint selection for ethephon. 19 20 According to the WOE document ( Kent 2006) " The OPP/ HED RfD Peer Review 21 Committee determined on February 10, 1994 that the reference dose ( RfD) should be based on 22 the 28 day study in human subjects ( MRID 00036510). Clinical signs of toxicity were observed 23 at 1.8 mg/ kg/ day ( only dose tested) and included diarrhea, urgency of bowel movements, urinary 24 urgency and stomach cramps." 25 26 A Report from EPA, Office of Pesticide Programs, Health Effects Division, Hazard 27 Identification and Assessment Review Committee ( HIARC) dated 4/ 1/ 98 states in reference to 28 the 28 day human study: " This human study is considered to be of better quality and the findings 29 more reliable than the 16 day human study previously used to define the RfD." Since 1994, the 30 HIARC has repeatedly ( 8/ 9/ 94, 4/ 1/ 98, 7/ 15/ 02 and 11/ 5/ 02) selected the 28 day human study to 31 assess all relevant exposure scenarios, and at the last HIARC meeting, a weight  of  evidence 32 comment regarding endpoint selection was included: " HIARC had considered experimental 33 animal studies on ethephon and concluded this human study was most appropriate for selection 34 of the endpoint of toxicity for risk assessment. The clinical signs of toxicity in this human study 35 occurred at dose levels that were much lower than seen in experimental animals." " Despite the 36 limitations of the study, and the equivocal nature of the reported findings, the HED ethephon risk 37 assessment team believes that, in the absence of data ruling out the observed effects as 38 inconsequential, the 28 day human study is the most appropriate study to use for assessing both 39 the acute and chronic dietary risks of ethephon." 40 41 The WOE document stated: " A number of conclusions relevant to endpoint selection can 42 be drawn from the database of ethephon oral toxicity studies in humans and animals: 43 ( 1) ethephon is neurotoxic in animal studies only at high doses ( 300 mg/ kg and above), ( 2) 44 ethephon inhibits blood cholinesterases, in particular plasma cholinesterase in animals and 45 humans at relatively low doses, ( 3) brain acetylcholinesterase is insensitive to ethephon in adult 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 51 of 69 animals. Accordingly, the team then debated whether to use effects in animals ( LOAEL 1 approximately 80 mg/ kg/ day) or in humans ( LOAEL of 1.8 mg/ kg/ day) for endpoint selection, 2 and opted as a matter of prudence to base endpoint selection on effects observed in humans." 3 The Board concluded that this is much lower than that expected from the animal studies, 4 however, the second study informs and provides the level of uncertainty to accept this LOAEL 5 and use it as a POD. 6 7 The WOE document concluded by stating: " The point of departure for the dietary 8 assessments use of a LOAEL was applied to the POD to obtain a reference dose of 0.06 9 mg/ kg/ day for assessment of both acute and chronic dietary risks was 1.8 mg/ kg/ day ( with an 10 uncertainty factor of 10x for intraspecies variability and a 3x factor for use of a LOAEL  )" 11 12 HSRB Consensus and Rationale 13 14 The ethephon 16 day human oral toxicity study ( second study) had no value on its own, 15 but it did inform the ethephon 28 day human oral toxicity study ( first study); it allows one to 16 consider the results of the first study in light of the information gained there from. The Board 17 approved the first study for use in EPA risk assessments, emphasizing that the scientific quality 18 is not adequate on its own, and that the dose level administered was almost certainly not the 19 lowest dose at which adverse effects are likely to be observed. However, its use in lieu of the 20 animal studies, will result in greater protection for exposed human populations. 21 22 6.2. Ethical considerations 23 24 Charge to the Board 25 26 In its ethics review of this research, EPA documented that the study reports contained 27 very little information concerning the ethical conduct of the research and that the available 28 information raised no ethical concerns. The Agency asks that the Board provide comment on the 29 following, taking into account all that is known about the ethical conduct of each study: 30 31 OPP's conclusion that there is not clear and convincing evidence that the conduct of the 32 research was fundamentally unethical; and 33 34 whether there is clear and convincing evidence that the conduct of the study was significantly 35 deficient relative to the ethical standards prevailing when the study was conducted. 36 37 Board Response to the Charge 38 39 Brief Overview of the Study 40 41 Two studies involving repeat high and low dose oral exposure of human subjects to 42 ethephon ( ethrel) were evaluated. Both studies were performed by Litton Bionetics, Inc. of 43 Bethesda, Maryland. The studies were sponsored by Amchem Products, Inc., of Ambler, 44 Pennsylvania. Both studies were conducted prior to publication of U. S. regulations ( drafted 45 1974, adopted by DHHS and FDA in 1981) or the Common Rule ( adopted by EPA in 1991), so 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 52 of 69 the regulatory standards established by 45 CFR 46 with respect to conduct of research involving 1 human subjects cannot be applied in this retrospective evaluation. The low dose study, however, 2 was performed after the 1972 Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) went 3 into effect, and is subject to the regulations contained therein. In particular, FIFRA Section 4 12( a)( 2)( P) states that "[ i] t shall be unlawful for any person   to use any pesticide in tests on 5 human beings unless such human beings ( i) are fully informed of the nature and purposes of the 6 test and of any physical and mental health consequences which are reasonably foreseeable 7 therefrom, and ( ii) freely volunteer to participate in the test." Both studies were also are expected 8 to be in compliance with the ethical standards for research involving human subjects established 9 by the 1964 version of the Declaration of Helsinki. 10 11 Critique of Study 12 13 The Board concurred with the factual observations of the strengths and weaknesses of the 14 study, as detailed in the EPA's Initial Ethics Review of Ethephon Human Study, dated March 17, 15 2006. However, further comments are warranted regarding: 1) whether the repeat high dose 16 oral exposure protocols used were designed to minimize risks to study participants; and 2) 17 whether the documentation and process of study subject enrollment was sufficient to meet 18 prevailing standards of voluntary informed consent. 19 20 1) Minimization of Risks to Study Participants 21 22 The two repeat high and low dose oral exposure studies were performed in 1971 and 23 1973, respectively. The high dose study involved repeated dosing, over a 28 day period, of 12 24 subjects ( six men and six women) with 1.8 mg/ kg body weight of ethephon per day by oral 25 ingestion. Four subjects ( two men and two women) received placebo control. The study 26 documents provide no clear justification for the selection of the 1.8 mg/ kg body weight dose, 27 other than passing reference to " a preliminary dose range study   carried out in two human 28 subjects. ( Litton 1972). 29 30 On weekdays, clinical symptoms were monitored continuously for eight hours following 31 ingestion of the test compound; after hours and on weekends, subjects were requested to self 32 report any adverse clinical symptoms. There was no mention in the documents reviewed by the 33 Board that the investigators made provision for observation or rescue during these off hours. 34 Laboratory analyses, including analysis of blood and urine samples, were performed weekly 35 during the study and also two weeks after last exposure. A large number of study subjects 36 receiving the active compound exhibited clinical symptoms clearly associated with ethephon 37 exposure, including diarrhea and other gastrointestinal disorders ( 4 participants), increased 38 frequency and urgency of urination ( 5 participants), and persistent abdominal pain ( 1 39 participant). Laboratory analyses also revealed transient elevations in blood glucose and 40 increased inhibition of plasma cholinesterase in subjects receiving ethephon. No stopping criteria 41 were listed in the final report, nor was there evidence that the investigators considered halting the 42 trial even after large numbers of study participants began to report adverse clinical symptoms. 43 44 The low dose study involved repeated dosing, over a 16 day period, of 20 subjects ( 10 45 men and 10 women) with 0.5 mg/ kg body weight of ethephon per day by oral ingestion. Ten 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 53 of 69 subjects ( six men and four women) received placebo control. The study documents again provide 1 no clear justification for the selection of the 0.5 mg/ kg body weight dose, other than indirect 2 reference to the high dose study described above. 3 4 As before, clinical symptoms were monitored continuously for eight hours and self 5 reported after hours and on weekends. Laboratory analyses were performed on days 1, 9, and 16, 6 and two weeks following last dose. No adverse clinical events were reported. Surprisingly, the 7 report even fails to mention that no adverse clinical events were seen, leading several Board 8 members to suspect that adverse event data was not rigorously collected. 9 10 2) Voluntary Informed Consent 11 12 Neither study contained sufficient information for the Board to adequately determine 13 whether or not the informed consent process used to enroll study participants met the standards 14 outlined in FIFRA Section 12( a)( 2)( P) and the 1964 version of the Declaration of Helsinki. Each 15 of the final study reports provided to the Board contained only but the briefest of statement as to 16 the nature of the voluntary informed consent process: 17 18 " Sixteen human volunteers judged to be in good health as ascertained by pre physical 19 interview, physical examination and selected clinical laboratory evaluations were chosen for the 20 study. All subjects were thoroughly briefed on the nature and present use of the test product, the 21 animal toxicity data, and the potential pharmacological side effects." 22 23 " All subjects were thoroughly informed on the nature and present use of the test 24 substance, the animal toxicity data, potential pharmacologic side effects, and the results of the 25 prior study in human volunteers. Based on this briefing, consent documents were obtained from 26 all subjects." 27 28 Although the 1973 low dose study does contain reference to written consent documents, 29 these were unavailable for review. 30 31 Despite the paucity of documentation, several Board members expressed concern over 32 what they consider to be potential violations of accepted standards of informed consent: 33 34   Circumstantial evidence suggests that employees of Litton Bionetics, Inc., may 35 have been enrolled as study participants. For example, there was mention of four 36 study participants " working in the same building." The possible participation of 37 employees in a laboratory directed research project raised issues of coercion and 38 voluntariness. 39   In the high dose study, a large number of study subjects receiving active 40 compound exhibited clinical symptoms clearly associated with ethephon 41 exposure, including diarrhea and other gastrointestinal disorders, increased 42 frequency and urgency of urination, and persistent abdominal pain. Not a single 43 study participant, however, withdrew from the study over the 28 day monitoring 44 period, regardless of the severity of illness. This again raised questions about the 45 voluntary nature of participation in research. 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 54 of 69 1 HSRB Consensus and Rationale 2 3 The Board concluded that: 4 5 a) The both the 28 and 16 day oral human toxicity studies failed to fully meet the specific 6 ethical standards prevalent at the time the research was conducted. 7 8 b) There was no clear and convincing evidence that the research is fundamentally 9 unethical intended to seriously harm participants or that informed consent was not obtained. 10 11 c) There was no clear and convincing evidence of significant deficiencies in the ethical 12 procedures could that have resulted in serious harm ( based on the knowledge available at the 13 time the study was conducted), nor that information provided to participants seriously impaired 14 their informed consent. 15 16 Although these two studies appear to lack justification for the dose selection, as well as 17 clear stopping criteria to prevent serious harm to research participants, the Board does not 18 believe that there was clear and convincing evidence that these studies could have resulted in 19 serious harm based on the knowledge available to the investigators at the time. 20 21 There were indications of informed consent deficiencies. Nevertheless, given the paucity 22 of information provided there was no evidence that the voluntary informed consent process used 23 in these two studies failed to meet the few regulatory and ethical standards applicable to research 24 conducted in 1971 1973. 25 26 The Board concluded that there was no obvious reason why the Agency cannot rely on 27 the results of this study, as appropriate under current pesticide laws, given the absence of clear 28 and convincing evidence that the research was fundamentally unethical or significantly deficient 29 relative to the ethical standards prevailing when the study was conducted. 30 31 7. Hydrogen Cyanide 32 33 Charge to the Board 34 35 When sodium cyanide is used as a fumigant, hydrogen cyanide is generated by 36 acidification. Because residues of HCN may remain on fumigated citrus, the Agency is 37 conducting an acute dietary risk assessment of hydrogen cyanide. 38 39 7.1. Scientific considerations 40 41 The Agency's WOE document describes a lack of data appropriate for developing an 42 acute dietary risk assessment for hydrogen cyanide. The WOE and DER present the results from 43 a clinical trial with amygdalin and the usefulness of this clinical trial in the acute dietary risk 44 assessment for hydrogen cyanide. The Agency has concluded that the clinical trial is appropriate 45 for establishing a point of departure in the acute dietary risk assessment for hydrogen cyanide. 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 55 of 69 1 Please comment on the scientific evidence that supports this conclusion. 2 3 Board Response to the Charge 4 5 Brief Overview of the Study 6 7 The clinical trial of amygdalin for treatment of cancer ( Moertel et al., 1982), which 8 included the preliminary pharmacology and toxicology study ( Moertel et al., 1981), involved the 9 administration, under controlled circumstances, of known amounts of amygdalin to patients with 10 terminal cancers for which no known treatments were available. Amygdalin was administered 11 intravenously for 21 days ( 4.5 g/ m2), followed by oral maintenance therapy of 500 mg ( three 12 times per day), plus a " metabolic therapy" consisting of diet, pancreatic enzymes, and vitamins. 13 Most patients were administered the standard dose regimen, but a small number received a high 14 dose regimen. 15 16 Clinical signs and symptoms consistent with cyanide toxicity ( nausea, vomiting, 17 headache, dizziness, mental obtundation) were observed in some patients following a single 500 18 mg oral dose of amygdalin. The conclusions regarding toxicity were based largely on several 19 patients who developed such symptoms when they took two 500 mg doses too close together or 20 ate foods such as raw almonds that are rich in ß glucosidase, an enzyme that causes the release of 21 cyanide from amygdalin. In such patients, the symptoms typically resolved when oral amygdalin 22 was discontinued, the dose was reduced, or the patients stopped eating the critical foods. In the 23 pharmacology and toxicology study, the responses of two patients challenged with almonds 24 provided further support for the conclusion that the symptoms reflected cyanide toxicity. In 25 some patients, the appearance of symptoms was associated with relatively high blood cyanide 26 levels, which in some instances approached levels observed in human fatalities (> 3 µ g/ mL). A 27 dose of 500 mg was interpreted as a minimal effect level but not as a NOAEL. 28 29 Critique of Study 30 31 The trial had several strengths. The sample size was large, including 178 patients. Blood 32 cyanide levels were assessed several times, at completion of intravenous ( i. v.) treatment, 48 33 hours after initiation of oral treatment, and at every subsequent evaluation. Measurements were 34 made two hours after the first morning dose of oral amygdalin, when the maximum elevation in 35 cyanide was anticipated. The trial employed a good operational definition of the clinical 36 outcome of interest in the trial, which was tumor progression. 37 38 The trial also had several weaknesses. First, it was not blinded and did not include a 39 placebo group. Second, insofar as the primary aim was to assess the effectiveness of amygdalin 40 as a treatment for advanced cancer, the assessment of potential cyanide toxicities was not as 41 systematic as the assessment of tumor progression. As in any clinical trial of drug efficacy, side 42 effects were recorded, however, these side effects were examined in relation to whole blood 43 cyanide levels. Oral dosing with amygdalin did not begin until 21 days of i. v. treatment had been 44 completed. It is unlikely that this introduced a bias, however. In contrast to delivery by oral 45 route, amygdalin delivered i. v. is largely excreted unchanged in urine without conversion to 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 56 of 69 cyanide. Whole blood cyanide levels were undetectable following i. v. dosing, making it likely 1 that the rise observed following oral dosing was not confounded by the prior i. v. dosing. Third, 2 patients who participated in the study were terminally ill with cancer. Although the inclusion 3 criteria required that patients be in " good general condition" and ambulatory, they are, 4 nevertheless, likely to represent a particularly sensitive subgroup, thus providing a conservative 5 estimate of the hydrogen cyanide dose at which toxicities occur. Fourth, all clinical signs and 6 symptoms of toxicity ( nausea, vomiting, headache, dizziness, mental obtundation, and 7 dermatitis) were observed with nearly equivalent frequencies during i. v. and oral dosing. Many 8 of these signs and symptoms might be increased in terminal cancer patients anyway, and thus 9 unrelated to amygdalin or cyanide. Moreover, if these were indications of toxicity related solely 10 to elevations in blood cyanide, they would not be expected to have occurred with equal 11 frequency during i. v. and oral dosing. The data from the natural experiments within the trial, 12 such as when the doses of individual patients who developed symptoms were changed or the 13 patients were challenged, provides the most persuasive evidence of an increased risk of cyanide 14 toxicity in patients administered amygdalin. 15 16 HSRB Consensus and Rationale 17 18 The Board concluded that data from the amygdalin trial could be used for establishing a 19 point of departure in the acute dietary risk assessment for hydrogen cyanide. 20 21 Despite its limitations, this study provides the best data we are likely to ever have on 22 which to establish a POD for this purpose. Given the severity of the effect, the steepness of the 23 dose response relationship, and the apparent inter individual differences in response to a given 24 dose, it would be imprudent to undertake an intentional dosing study of healthy humans in order 25 to establish a LOAEL and NOAEL for hydrogen cyanide. 26 27 7.2 Ethical considerations 28 29 Charge to the Board 30 31 In its ethics review of this research, EPA did not identify any deficiencies with respect to 32 the ethical conduct of this research. The Agency asks that the Board provide comment on the 33 following, taking into account all that is known about the ethical conduct of this study: 34 35 OPP's conclusion that there is not clear and convincing evidence that the conduct of the 36 research was fundamentally unethical; and 37 38 whether there is clear and convincing evidence that the conduct of the study was 39 significantly deficient relative to the ethical standards prevailing when the study was conducted. 40 41 Board Response to the Charge 42 43 Brief Overview of the Study 44 45 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 57 of 69 Two related studies are being evaluated. Both were sponsored by the National Cancer 1 Institute. The first study was a pharmacologic and toxicological study involving six subjects 2 which took place at the Mayo Clinic ( Rochester, MN), with the results being published in the 3 Journal of the American Medical Association in 1981 ( the Board assumed the study was 4 conducted 1979 1980). Although the published report does not describe the ethical standards to 5 which the researchers adhered, the Board assumed that as a federally funded study, the research 6 would have been subject to the then current version of the federal DHHS [ DHEW] regulations 7 ( 45 CFR Part 46) that would later become the Common Rule. The second study was essentially a 8 Phase II follow up to the first study, involving 178 subjects who were enrolled at four sites 9 ( Mayo Comprehensive Cancer Center, Mayo Clinic, Rochester, MN; UCLA Johnson 10 Comprehensive Cancer Center, Los Angeles, CA; Memorial Sloan Kettering Cancer Center, 11 New York, NY; and University of Arizona Cancer Center, Tucson, AZ). The results of that 12 second study were published in the New England Journal of Medicine in 1982. That article also 13 does not specify the specific ethical rules under which the study was conducted, and this Board 14 again assumes that it would have been subject to the then current version of the predecessor 15 regulations ( DHHS [ DHEW], 45 CFR Part 46) to the current Common Rule. 16 17 Critique of Study 18 19 The Board concurred with the factual observations about the study, as detailed in Carley 20 ( 2006h). 21 22 In particular, the Board concurred with the key observation regarding the difference 23 between this study and the other studies that the Board has heretofore been asked to review. This 24 study involved testing a compound for its safety and efficacy in treating a medical problem. As 25 such, the ethical evaluation of this study was significantly different from that of a study 26 involving exposing subjects to a pesticide. A major consideration in evaluating the ethics of such 27 a study involved determining whether the two arms of the study were in clinical equipoise, a 28 concept that was only in its earliest stages at the time of this study. Nonetheless, it does appear 29 that this study would meet even the modern day understanding of that concept. All of the 30 subjects were persons with histologically proven cancer for which no standard treatment was 31 known to be available. The subjects received either a standard dose or a high dose of amygdalin 32 ( Laetrile). Prior to this study being conducted, there was substantial uncertainty regarding 33 whether this compound might indeed be a safe and effective treatment for many forms of cancer. 34 As stated in the New England Journal of Medicine article, it had " eclipsed any other unorthodox 35 therapy ever used for any disease in our time." Thus, conducting this study served to answer an 36 important medical question of that time period. 37 38 Moreover, the published report of the second study indicated compliance with all of the 39 procedural protections that would be required today. It notes that all " patients were fully 40 informed about the experimental and unorthodox nature of the treatment program as well as any 41 possible alternative treatment available to them. A signed form giving informed consent, 42 approved by the Human Subjects Committee at each of the four participating centers, was 43 obtained from each patient." ( The actual forms were not available for review by the Board.) The 44 article further noted that " the methods of this trial were entirely comparable to those employed in 45 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 58 of 69 studies of any new agent being developed and tested for cancer treatment through more 1 traditional channels." 2 3 HSRB Consensus and Rationale 4 5 The Board concluded that: 6 a) The hydrogen cyanide human oral toxicity study appeared to meet the specific ethical 7 standards prevalent at the time the research was conducted. 8 9 b) There was no evidence that the research was fundamentally unethical intended to 10 seriously harm participants or that informed consent was not obtained. 11 12 c) There was no evidence of significant deficiencies in the ethical procedures that could 13 have resulted in serious harm ( based on the knowledge available at the time the study was 14 conducted) nor that information provided to participants seriously impaired their informed 15 consent. 16 17 Although the Board based its determinations only on the two published articles, it did not 18 find any ethical flaws in the conduct of these two studies. The article described appropriate 19 informed consent procedures. The risks and potential benefits of the dosing were appropriate for 20 a medical treatment study for this particular cancer population. 21 22 The Board concluded that there was no obvious reason why the Agency cannot rely on 23 the results of this study, as appropriate under current pesticide laws, given the absence of clear 24 and convincing evidence that the research was fundamentally unethical or significantly deficient 25 relative to the ethical standards prevailing when the study was conducted. 26 27 8. Amitraz 28 29 Charge to the Board 30 31 Exposure to amitraz can result in neurotoxicity as evidenced by clinical signs such as 32 ataxia, ptosis, emesis, labored respiration, muscular weakness, tremors, hypothermia and 33 bradycardia. The Agency is conducting an aggregate ( single chemical, multi route) risk 34 assessment of amitraz. 35 36 8.1. Scientific considerations 37 38 The Agency's WOE document and DERs for amitraz describe the study design and 39 results of the amitraz acute oral and dermal toxicity human studies and the human metabolism 40 study. The WOE document also discusses the Agency's conclusions regarding the usefulness of 41 the human studies in the single chemical risk assessment for acute and chronic oral exposures in 42 addition to dermal and inhalation exposures of various durations. For oral exposure, the Agency 43 has concluded that the combined results from the single oral dose study and human metabolism 44 study establishes a dose response relationship in human subjects and that the single oral dose 45 study is appropriate for developing a point of departure for acute and chronic dietary risk, short 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 59 of 69 term oral exposure, and inhalation exposures of various durations. The Agency has further 1 concluded that the human dermal study is appropriate for developing a point of departure for 2 dermal exposures of various durations. 3 4 Please comment on the scientific evidence that supports these conclusions. 5 6 Board Response to the Charge 7 8 Overview 9 10 The HSRB was asked to comment on the scientific evidence that supports the following 11 conclusions: 12 13 1. For oral exposure, the Agency concluded that the combined results from the 14 single oral dose study and human metabolism study establish a dose response relationship in 15 human subjects, and that the single oral dose study is appropriate for developing a point of 16 departure for acute and chronic dietary risk, short term oral exposure, and inhalation exposures 17 of various durations. 18 19 2. The Agency further concluded that the human dermal study is appropriate for 20 developing a point of departure for dermal exposures of various durations. 21 22 Amitraz [ N'( 2,4 dimethylphenyl) N[[( 2,4 dimethylphenyl) imino] methyl] N 23 methylmethanimidamide] is an insecticide/ acaricide with wide range of registered uses in the 24 United States. The toxicity profile for amitraz has not been characterized completely, especially 25 developmental and reproductive effects. Neurotoxicity is considered the most sensitive effect 26 resulting from exposure to amitraz. Neurotoxicity has been demonstrated in multiple species 27 ( baboon, cat, dog, mouse, rat and rabbit). Clinical signs include central nervous system 28 depression, ataxia ( loss of coordination), ptosis ( droopy eyelids), emesis ( vomiting), labored 29 respiration, muscular weakness, tremors, hypothermia and bradycardia ( slow heartbeat). Similar 30 signs are seen in humans. The Agency's evaluation of amitraz included three human studies: a 31 1984 oral dose metabolism study Campbell 1984), a 1992 oral dose tolerance study ( Cass 1992) 32 and a 1997 dermal dose tolerance study ( Langford 1997). 33 34 Critique of Oral Dose Metabolism Study ( 1984) 35 36 Radio labeled amitraz was orally administered to rats, mice, baboons and humans. The 37 two human volunteers received a single 0.25 mg/ kg dose of amitraz by capsule. This dose caused 38 dry mouth, drowsiness, disorientation, decreased temperature, bradycardia, and slightly pale 39 appearance in both subjects, persisting up to 12 hours after dosing. One subject fell asleep for 6 40 hours following dosing. Psychomotor testing was not included in the protocol. Approximately 41 44% of the dose was excreted within 12 hours, with 63% excreted within 24 hours. Study 42 deficiencies included the small number of subjects ( N= 2), testing of males only, and no control 43 group. Sex differences in the repeat dose animal studies have shown that females are more 44 sensitive than males. The study investigators concluded that humans were more sensitive to 45 amitraz than were other species included in the metabolism study. 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 60 of 69 1 The occurrence of multiple signs and symptoms in both subjects and the continued 2 bradycardia up to 12 hours post dosing suggest that the 0.25 mg/ kg dose was not the lowest 3 adverse effect level for amitraz in humans. Because there was only one dose level, it was not 4 possible to glean any information regarding dose response from this study. Incomplete excretion 5 of the amitraz metabolites at 24 hours post dosing suggests that some portion of the dose was 6 present on the day following dosing, albeit not at levels sufficient to produce the frank signs and 7 symptoms observed on the day of dosing. 8 9 Critique of Single Oral Dose Study ( 1992) 10 11 The design was a single oral dose double blind tolerance study. The primary objective of 12 this study was to determine the tolerance of male volunteers to a single dose of amitraz at two 13 different dose levels ( 0.0625 and 0.125 mg/ kg), with a placebo control. Six subjects completed 14 the study. Each subject received each of the doses and the placebo. Dosing events were separated 15 by at least 14 days for each subject. The dosing regimen was thoughtfully constructed, beginning 16 with the lower dose, and moving to the higher dose when it was observed that the lower dose 17 was well tolerated. The subjects were admitted to a clinical pharmacology unit the evening 18 before each dosing and remained there for 36 hours. Complete physical examinations were 19 conducted before and after the study. The subjects were followed for at least three weeks 20 following the study. The most sensitive neurologic endpoints measured in this study were two 21 psychomotor performance tests: choice reaction time and critical flicker fusion threshold. The 22 psychomotor performance tests were administered pre dose, 2.5 hours, and 8 hours following 23 dosing. The report provides tabular and graphic representation of the results of these tests, but no 24 statistical analyses were conducted. Study deficiencies included the small number of subjects 25 ( N= 6), and the testing of males only. The study investigators concluded that no effects were 26 observed from the single oral dose in any of the subjects. 27 28 The major concern with this study was whether " no effect" was truly observed. The study 29 report was deficient in its description of the psychomotor performance testing, and in the 30 rationale for selecting these tests. There were no descriptions of the specific procedures followed 31 for the psychomotor tests, no standard operating procedures, and no quality assurance 32 documentation. Also, there was no evidence provided in the report to indicate that these tests 33 were the most sensitive available. A review of the current scientific literature, and discussions 34 with leading scientists in this area of expertise would permit the Agency to determine if these 35 psychomotor test results are adequate to characterize a " no effect" level in regard to 36 neurotoxicity for amitraz. 37 38 Critique of Dermal Toxicity Study ( 1997) 39 40 This study was a double blind sequential dosing study with a randomized crossover and a 41 placebo group. The study aims were to 1) establish a no effect level for acute effects following 42 repeated dermal doses of amitraz, 2) produce data that would permit calculation of margins of 43 safety for agricultural workers. Eight male volunteers were given a total dose of either 0, 8, 16 or 44 24 mg/ kg amitraz, applied dermally as four equal doses of 0, 2, 4 or 6 mg/ kg in an aqueous 1: 1 45 ( w/ w) slurry every 2.5 hours over 10 hours. Starch, 1: 1 ( w/ w) in water, was used as a placebo. 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 61 of 69 Each of these amitraz experiments involved a timed series of dosing events ( 0, 2.5, 5.0, and 7.5 1 hours), followed by a washing event at 10 hours. Each dose within an experiment was applied to 2 a different 20 cm2 skin surface area, so the total skin surface treated in each experiment was 80 3 cm2. Thus, skin loadings for the three experiments were 7,000, 14,000, and 21,000 µ g/ cm2, 4 corresponding to the three dose levels ( 8 mg/ kg, 16 mg/ kg, 24 mg/ kg), assuming a body weight 5 of 70 kg. No differences were observed between treatment and placebo for any of the measured 6 endpoints. No urinary metabolite monitoring was conducted to confirm that amitraz had been 7 absorbed. The study report is deficient in its description of the psychomotor performance testing, 8 and in the rationale for selecting these tests. There is no description of the specific procedures 9 followed, no standard operating procedures, and no quality assurance documentation. Also, there 10 is no evidence provided in the report to indicate that these tests were the most sensitive available. 11 A review of the current scientific literature, and discussions with leading scientists in this area of 12 expertise would permit the Agency to determine if these psychomotor test results are adequate to 13 characterize a " no effect" level in regard to neurotoxicity for amitraz. 14 15 The primary deficiency of this study is that it does not provide a realistic worker 16 exposure scenario; that is, the exposures of the subjects in these experiments did not correspond 17 to exposures likely to be seen among workers. Large amounts of amitraz ( 140 420 mg) were 18 applied to a relatively small skin surface area ( 80 cm2) in the experiments, whereas we typically 19 see much larger skin surface areas exposed to smaller amounts among workers. For example, the 20 hands, a skin surface commonly exposed to pesticides, have a total surface area of 990 cm2, or 12 21 times greater than the exposed skin surface area in this experiment ( USEPA 1997). If both the 22 hands and forearms were exposed, the total exposed surface area would be 3,900 cm2, or 49 23 times the surface area exposed in this study. This discrepancy is important, as it has a major 24 impact on the amount of compound that can be absorbed within a defined time period. Dermal 25 dosing studies require careful consideration of three factors: mass applied to the skin, surface 26 area treated, and the duration of exposure. These three factors are typically used to determine the 27 flux of a chemical through the skin ( e. g., mg/ cm2/ hr). Percent absorbed is highly dependent on 28 the skin loading, or mass applied per unit area ( e. g., mg/ cm2). The relationship between skin 29 loading and percent absorbed was made clear in a review of studies in the rat by Zendzian 30 ( 2000). In the case of azinphos methyl, for example, a loading of 3 nanomole/ cm2 for 10 hours 31 resulted in 23% absorption, a loading 10 fold higher ( 29 nmolesM/ cm2) resulted in 15% 32 absorption, and a further 10 fold increase in loading ( 293 nmoles/ cm2) resulted in only 2.9% 33 absorption. These azinphos methyl loadings, expressed as mass per unit area, were 0.95, 9.2, and 34 93 µ g/ cm2, respectively. In earlier dermal dosing studies involving humans, radio labelled 35 pesticides were applied at loadings of 4 and 40 µ g/ cm2 ( Feldmann and Maibach 1974). It is 36 evident that the skin loadings in the amitraz study were several orders of magnitude higher than 37 those used in the above cited studies. The key point is that chemical loadings on small areas of 38 skin result in relatively small amounts of chemical absorbed. In this dermal toxicity study, the 39 loadings were so high that the three " dose" levels were essentially equivalent in terms of dermal 40 absorption potential. 41 42 If it is assumed that the flux of amitraz in these experiments was approximately 2 43 µ g/ cm2/ hr, as has been estimated from a study of chlorpyrifos, a lipophilic insecticide with a 44 similar molecular weight ( Nolan et al. 1984), then the total mass absorbed in the amitraz 45 experiments over 10 hours would have been approximately 1,000 µ g ( 1 mg), or an absorbed dose 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 62 of 69 of 0.014 mg/ kg. If this same flux were applied to an exposure to the hands and forearms of a 1 worker, the total mass absorbed would be approximately 50,000 µ g ( 50 mg), or an absorbed dose 2 of 0.71 mg/ kg, well above both the 0.125 mg/ kg single oral dose " no effect" level, and the 0.25 3 mg/ kg single oral dose that elicited multiple signs and symptoms of neurotoxicity. It is for this 4 reason that the amitraz dermal toxicity study cannot be considered a " no effect" study for risk 5 assessment purposes. 6 7 HSRB Consensus and Rationale 8 9 a. The Board concluded that the results from the single oral dose study are informed by 10 the human metabolism study such that the single oral dose study is appropriate for developing a 11 point of departure for acute and chronic dietary risk and short term oral exposure. 12 13 The appearance of overt signs and symptom of toxicity in the 1984 oral metabolism study 14 at a dose of 0.25 mg/ kg provides some confidence that the highest dose ( 0.125 mg/ kg) in the 15 1992 single oral dose study represent a no observable adverse effect level ( NOAEL) for an acute 16 dietary exposure to amitraz No effects of neurologic toxicity were observed in any of the study 17 subjects at 0.125 mg/ kg. This conclusion rests on the assumption that the psychomotor tests 18 applied to the subjects are the most sensitive endpoints for neurotoxicity, and that they were 19 conducted properly. There was considerable uncertainty regarding these psychomotor tests, as 20 the procedures used were not described in the study, and on quality assurance information was 21 provided. Thus, the findings from this study should be used with caution for risk assessment 22 purposes. 23 24 b. The Board concluded that the combined results from the single oral dose study and the human 25 metabolism study were not appropriate for developing a point of departure for chronic dietary 26 risk, short term oral exposure, or inhalation risk. 27 28 A single oral dose of 0.25 mg/ kg elicited frank symptoms of toxicity in both subjects in 29 the 1984 metabolism study. Multiple signs and symptoms were observed in the subjects for 30 several hours post dosing, and at least one sign ( bradycardia) was still present at 12 hours post 31 dose. Excretion of radio labeled metabolites was incomplete ( 62%) at 24 hours. The proposed 32 NOAEL is only one half the dose used in the 1984 study. Thus, subjects exposed to repeated 33 daily doses, as would occur in short term or chronic oral dose studies, would achieve a 34 cumulative dose of 0.25 mg/ kg within 48 hours. It seems quite possible that repeated short term 35 oral exposures or chronic oral exposures would elicit at least some effects in humans within a 36 very few days. Thus, the available data do not demonstrate a no effect level for multi day oral 37 exposures. In regard to inhalation exposures, absorption through the respiratory tract is generally 38 more efficient than absorption through the gastro intestinal tract. It is quite possible that adverse 39 effects would have been observed in an inhalation exposure study that delivered 0.125 mg/ kg as 40 a single dose. Also, an oral dose study would not capture adverse effects unique to exposure by 41 the inhalation route. Thus, the available data do not demonstrate that the oral NOAEL and the 42 inhalation NOAEL are equivalent. 43 44 c. The majority of the Board concluded that the human dermal study was not appropriate 45 for developing a point of departure for dermal exposures of various durations. 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 63 of 69 1 The HSRB members did not consider the dermal toxicity study to be a valid scientific 2 study for risk assessment because: 1) the study involved extremely high loadings ( mass per unit 3 surface area) of amitraz on the skin, making the three dose levels used in the study very nearly 4 equivalent in regard to dermal absorption potential, and not equivalent to worker exposure 5 scenarios; 2) the study did not demonstrate an effect ( i. e., the study was equivalent to a 6 " NOAEL only" study); and 3) there was no corroborating evidence to demonstrate that an 7 internal dose had been delivered to the subjects by the dermal route. One member of the HSRB, 8 while agreeing with these scientific criticisms, considered that the study might still be of use to 9 the Agency. 10 11 8.2. Ethical considerations 12 13 Charge to the Board 14 15 a. The Agency requests that the Board provide comment on the following: 16 17 With respect to the Campbell ( 1984) research, whether the lack of medical surveillance of 18 subjects, following the termination of dosing, to establish that subjects' signs of adverse effects 19 had returned to normal should be considered significantly deficient relative to the ethical 20 standards prevailing when the study was conducted; and 21 22 With respect to the Cass ( 1992) and the Langford ( 1998) studies, whether references to 23 the test material as a drug and other statements that could indicate the study constituted medical 24 research, that appear in the materials used to obtain informed should be considered significantly 25 deficient relative to the ethical standards prevailing when the study was conducted; and 26 27 b. The Agency asks that the Board provide comment on the following, taking into account all 28 that is known about the ethical conduct of each study: 29 30 OPP's conclusion that there is not clear and convincing evidence that the conduct of the 31 research was fundamentally unethical. 32 33 Whether there is clear and convincing evidence that the conduct of the study was 34 significantly deficient relative to the ethical standards prevailing when the study was conducted. 35 36 Board Response to the Charge 37 38 The compound amitraz is an alpha two adrenergic agonist that produces sympatholytic 39 effects leading to sedation and other neurological signs and symptoms, as well as cardiovascular 40 depression with a drop in blood pressure and heart rate. The studies under ethical review include 41 two metabolic studies in 1984 using C14 radio labeled isotope technology, a 1992 oral dosing 42 study, and a 1998 dermal absorption study. 43 44 The two metabolic studies were performed in 1984 and involved two volunteer subjects. 45 The oral dosing study was performed in 1992 and involved six research subjects ( with an 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 64 of 69 additional ( 1) subject withdrawn for an unrelated rash). The oral dosing study was a double 1 blind, randomized, placebo controlled, crossover study involving two different doses. The oral 2 dosing study progressed in three phases, escalating from the lower dose to the higher dose. The 3 protocol stated that the research was in compliance with the 1989 version of the Declaration of 4 Helsinki, an early version of good clinical practice ( GCP) guidelines promulgated by the EMEA 5 ( 111 3976 88 EN), the ABPI Guidelines for Medical Experiments in Non Patient Human 6 Volunteers ( 1988, 1990), the 1986 RCP Guidelines on Research Using Healthy Volunteers, the 7 FDA Compliance Program for Drugs and Biologics and the GCP guidelines from Japan that 8 were current in 1992 ( Notification No. 874 from the Ministry of Health and Welfare). The 9 approval of the research ethics committee was given on November 20, 1991, but no information 10 was provided about the substance and process of that review. 11 12 The dermal absorption study was performed in 1998 and involved eight research subjects. 13 The study was a double blind, randomized, placebo controlled, crossover study involving three 14 different doses ( in a four phase dose escalation design). The protocol stated that the research was 15 in compliance with the above standards, with the updated GCP guidelines promulgated in 1996. 16 The approval of the research ethics committee was given on December 22, 1997, although no 17 information is provided about the substance and process of that review. 18 19 Critique of Study 20 21 The Board concurred with the factual observations of the strengths and weaknesses of the 22 two 1984 metabolic studies, as detailed in Carley ( 2006g). Specifically, there is no justification 23 for the dose selection, no record of independent committee review, and no record of informed 24 consent ( other than the description of the participants as volunteers. The dose selected did result 25 in adverse events as might be expected from the administration of a product with this 26 pharmacological profile. The period of recorded observations was eight hours, and stated 27 observation time was 12 hours. Although the period of observation was insufficient to assure 28 that the physiologic condition of the volunteers had returned to baseline, the known physiologic 29 effects of the compound are such that the period of observation was sufficient to assure the lack 30 of significant adverse effects. 31 32 The Board concurred with the factual observations of the strengths and weaknesses of the 33 1992 oral dosing study as documented in Carley ( 2006h). Of note was that the volunteer 34 information included information about the risks of the administration of the study compound 35 which were relatively complete in the scope of the risks described ( yet absent a few details 36 within each organ system). 37 38 The Board concurred with the factual observations of the strengths and weaknesses of the 39 1998 dermal absorption study, as documented in Carley ( 2006i). Although concern has been 40 expressed about the choice of dose, the study design involved a dose escalation such that adverse 41 events at lower doses could have been anticipated. 42 43 HSRB Consensus and Rationale 44 45 The Board concluded that: 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 65 of 69 1 a) The amitraz acute oral and dermal human toxicity studies failed to fully meet the specific 2 ethical standards prevalent at the time the research was conducted. 3 4 b) There was no clear and convincing evidence that the research was fundamentally unethical 5 intended to seriously harm participants or that informed consent was not obtained. 6 7 c) There was no clear and convincing evidence of significant deficiencies in the ethical 8 procedures that could have resulted in serious harm ( based on the knowledge available at the 9 time the study was conducted), nor that information provided to participants seriously impaired 10 their informed consent. 11 12 Although the Board concurred in the noted deficiencies with the 1984 metabolic studies, 13 the Board did not consider the lack of documentation of medical supervision following the 14 termination of dosing in the 1984 metabolic studies to be significantly deficient relative to the 15 ethical standards prevailing when the study was conducted. 16 17 The Board also acknowledged the observations that the 1992 oral dosing study and the 18 1998 dermal absorption study includes potentially misleading references in the informed consent 19 documents. However, the Board does not believe that these deficiencies could have resulted in 20 serious harm based on the knowledge available to the investigators at the time, nor seriously 21 impaired the informed consent of the research subjects. As such, the Board did not consider these 22 findings significantly deficient relative to the ethical standards prevailing when the study was 23 conducted. 24 25 The Board concurred with the assessment of the Agency that there was not clear and 26 convincing evidence that the conduct of the research was fundamentally unethical. The research 27 as designed and conducted was not intended to seriously harm participants nor failed to obtain 28 informed consent. Thus, the Board concluded that there was no ethical objection to the 29 appropriate use of the data from these studies ( as discussed in the scientific assessment) given 30 the absence of clear and convincing evidence that the research was fundamentally unethical or 31 significantly deficient relative to the ethical standards prevailing at the time. 32 33 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 66 of 69 REFERENCES 1 2 Campbell J. 1984. A Comparison of The Metabolism of ( 14c) AMITRAZ in Rats, Mice, 3 Baboon and Human . FBC Limited. EPA Trid No 350109 025. 20 Pages 4 5 Carley. 2006a. United States Environmental Protection Agency Initial Ethical Review of 6 Aldicarb Human Study. 7 8 Carley J. 2006b. United States Environmental Protection Agency, Initial Ethics Review of 9 Methomyl Human Study. REF: McFarlane, P., Sanderson, J., Freestone, S. 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Inveresk Clinical Research Limited File 8889, ICR 013580 7 634 Pages. 8 9 McFarlane, P.; Sanderson JB and Freestone, S. 1998. A Randomised Double Blind Ascending 10 Oral Dose Study with Methomyl: Lab Project No. HLO 1998 00969. Unpublished study 11 prepared by Inveresk Clinical Research. MRID 44721401. 12 13 Moertel, CG et al. 1981 A Pharmacologic and Toxicological Study of Amygdalin. JAMA, Vol. 14 245, No. 6: 591 594, MRID # 46769601, published. 15 16 Moertel, C,; Fleming, T.; Rubin, J.; et al. 1982. A Clinical Trial of Amygdalin ( laetrile) in the 17 Treatment of Human Cancer. The New England Journal of Medicine: 306( 4): 201 206. 18 MRID 46769602. 19 20 Moyer J, Milanez S and Ross R. 1998, Toxicology & Hazard Assessment Group Life Sciences 21 Division. November, 1998. Methomyl/ 90301 Non Guideline Study Study Type: Ascending 22 Acute Oral Toxicity Study in Humans MRID 44721401 Health Effects Division Office of 23 Pesticide Programs. 24 25 Moyer J and Milanez S. Toxicology and Hazard Assessment Group Life Sciences Division. 26 Oxamyl/ 103801 Non Guideline Study. Study Type: Ascending Oral Toxicity Study in Humans. 27 MRID 44912301. Health Effects Division Office of Pesticide Programs USEPA. 13 Pages 28 29 Nolan RJ, Rick DL, Freshour NL, Saunders JH. 1984. Chlorpyrifos: pharmacokinetics in human 30 volunteers. Toxicol Appl Pharmacol. 73: 8 15. 31 32 NRC 2001. Intentional Human Dosing Studies for EPA Regulatory Purposes. National 33 Academy Press. 34 35 Reese, W. 1972. Oral Study   Humans; None Guideline Citation: Reese, W. H ( 1972) Final 36 Report  Phase II: Evaluation of Ethrel in Human Volunteers: BRL Project No. 7223. Prepared 37 by Litton Industries, submitted by Union Carbide Agricultural Products, Co. CDL: 093946 D 38 March 3, 1972. MRID 00036510 39 40 Sette W. 1992. Aldicarb Oral Toxicity Study in Humans. Data Evaluation Report. United 41 States Environmental Protection Agency. 42 43 USEPA. 2000. Office of Pesticide Programs Science Policy on The Use of Data on 44 45 USEPA. 1997. Exposure Factors Handbook. U. S. Environmental Protection Agency. 46 Proposed Final Draft V. 1. Dated May 16, 2006; Do Not Cite or Quote 69 of 69 1 2 Weir. 1997. Oral Study   Humans: Non Guidline   Citation: Weir, R. J. ( 1977) Final Report; 3 Evaluation of Ethephon in Human Volunteers: LBI Project No. 2416. Prepared by Litton 4 Bionetics, Inc. MRID 00066931. 5 6 Wyld, PJ., Watson CE, Nimms, WS and Watson N. 1992. A Safety and Tolerability Study of 7 Aldicarb at Various Dose Levels in Healthy Male and Female Volunteers. Inveresk Clinical 8 Research Report No. 7786. Project No. 003237. 372 Pages. 9 10 Zendzian RP. 2001. Dermal absorption of pesticides in the rat. American Industrial Hygiene 11 Association Journal. 61: 473 483. 12


Comment Info: =================

General Comment:Dear Mr. Zeller:

I am writing as an individual consumer to request an extension of the comment period for the Food and Drug Administration's ("FDA") Proposed Rule Deeming Tobacco Products to be Subject to the Federal Food, Drug, and Cosmetic Act, as amended by the Family Smoking and Prevention and Tobacco Control Act (the "Proposed Rule") published at 79 Fed. Reg. 23,142 and Federal Register No. 2014-09491. On behalf of myself, I am requesting that the comment period for the Proposed Rule be extended by the FDA for an additional 105 days, from its current 75-day period, to 180 days.

The Proposed Rule raises a number of significant issues and questions that are important and relevant to me, as a consumer of products that are proposed for regulation under the Proposed Rule. The Proposed Rule asks about a hundred different questions I might want to respond to. I want to provide my thoughts and comments on many of these issues, but my time to devote to researching and providing thoughtful comments on these important questions is limited. I have already spent many hours researching and dissecting these issues, but they take time. I know that the FDA took many years to even come up with the Proposed Rule, so I do not think it is at all unreasonable to allow the public a mere six months to comment on it. This is our only opportunity, as consumers, to provide our feedback.

I feel very strongly about e-cigarettes as an alternative to combustible tobacco cigarettes. Quite simply, they are the best alternative and saved me many of my own health issues. I wish to provide you with my personal story, as well as science- and evidence-based responses to your questions so that you can take my comment into account. I realize that the FDA has the authority under 21 CFR 10.40 to extend this time frame and that the FDA has exercised this authority on numerous occasions in the past. I would therefore ask that you do so here, so that all stakeholders have the opportunity to provide their comments on this proposed regulation.

I appreciate your consideration of my request and am happy to discuss this issue with you further.  I would like to believe that the average citizen still has a say regarding the regulation of what we freely choose to consume.

Sincerely,

A concerned consumer


[Federal Register Volume 82, Number 146 (Tuesday, August 1, 2017)]
[Rules and Regulations]
[Pages 35654-35655]
[FR Doc No: 2017-16151]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 100

[Docket No. USCG-2017-0673]

Special Local Regulations; SUP3Rivers the Southside Outside,
Pittsburgh, PA

AGENCY: Coast Guard, DHS.

ACTION: Notice of enforcement of regulation.

-----------------------------------------------------------------------

SUMMARY: The Coast Guard will enforce a special local regulation for
navigable waters of the Allegheny and Monongahela Rivers during the
SUP3Rivers the Southside Outside event. This regulation is needed to
provide for the safety of life during the marine event. During the
enforcement period, entry into this regulated area is prohibited to all
vessels not registered with the sponsor as participants or official
patrol vessels, unless specifically authorized by the Captain of the
Port Marine Safety Unit Pittsburgh (COTP) or a designated
representative.

DATES: The regulations in 33 CFR 100.801, Table 1, Sector Ohio Valley,
line 29, will be enforced from 6:30 a.m. through 11:30 a.m. on
September 2, 2017.

FOR FURTHER INFORMATION CONTACT: If you have questions about this
notice of enforcement, call or email MST1 Jennifer Haggins, Marine
Safety Unit Pittsburgh, U.S. Coast Guard; telephone

412-221-0807, email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: The Coast Guard will enforce a special local
regulation for the annual SUP3Rivers the Southside Outside event listed
in 33 CFR 100.801, Table 1, line 29, from 6:30 a.m. through 11:30 a.m.
on September 2, 2017. Entry into the regulated area is prohibited
unless authorized by the Captain of the Port Marine Safety Unit
Pittsburgh (COTP) or a designated representative. Persons or vessels
desiring to enter into or pass through the area must request permission
from the COTP or a designated representative. If permission is granted,
all persons and vessels shall comply with the instructions of the COTP
or designated representative.
    This notice of enforcement is issued under authority of 33 CFR
100.801 and 5 U.S.C. 552 (a). In addition to this notice in the Federal
Register, the Coast Guard will provide the maritime community with
advance notification of this enforcement period via Local Notice to
Mariners and updates via Marine Information Broadcasts.

    Dated: July 25, 2017.
L. McClain, Jr.,
Commander, U.S. Coast Guard, Captain of the Port Marine Safety Unit
Pittsburgh.
[FR Doc. 2017-16151 Filed 7-31-17; 8:45 am]
BILLING CODE 9110-04-P


Fertilizer Facilities Reporting Discharges of Phosphorus Compounds to PCS for 2002 NPID Name City Total Facility Phosphorus Load % of Total Phosphorus Load for Category Cummulative % of Total Phosphorus Load for Category MS0003115 MISSISSIPPI PHOSPHATES CORP PASCAGOULA 5,798,186 94.9% 94.9% Anomaly  loads delete LA0029769 IMC PHOSPHATES CO  FAUSTINA DONALDSONVILLE 299,857 4.9% 99.8%

OK0029149 TERRA NITROGEN, L. P. VERDIGRI CATOOSA 5,589 0.1% 99.9%

OK0021024 KOCH NITROGEN CO. ENID NITROGN ENID 4,245 0.1% 99.9%

OK0036161 TERRA NITROGEN CORP. WOODWARD WOODWARD 2,458 0.0% 100.0%

MS0027995 VICKSBURG CHEMICAL COMPANY VICKSBURG 1,389 0.0% 100.0%

FL0001643 NITRAM CHEM TAMPA TAMPA 44 0.0% 100.0%

Total Fertilizer Phosphorus Load 6,111,768 ted Pulp and Paper Mills Reporting Discharges of Phosphorus Compounds to PCS for 2002 NPID Name City Total Facility Phosphorus Load % of Total Phosphorus Load for Category Cummulative % of Total Phosphorus Load for Category VA0003646 MeadWestvaco Packaging Resourc Covington 202,413 7.07% 7.07%

AL0002674 WEYERHAEUSER CO PINE HILL 194,295 6.79% 13.86%

FL0000876 BUCKEYE FLORIDA PERRY 191,457 6.69% 20.56%

VA0004162 International Paper  Franklin Franklin 177,302 6.20% 26.75%

AL0000396 INTERNATIONAL PAPER CO COURTLAND 161,880 5.66% 32.41%

NC0000680 Weyerhaeuser Co Plymouth Ml Plymouth 130,411 4.56% 36.97%

OR0000558 SP NEWSPRINT NEWBERG 125,175 4.37% 41.34%

WI0003620 DOMTAR PORT EDWARDS 110,063 3.85% 45.19%

AL0003158 BOWATER ALABAMA INC COOSA PINES 93,933 3.28% 48.47%

ID0001163 POTLATCH CORP LEWISTON 90,889 3.18% 51.65%

MN0001643 BOISE CASCADE CORP INTERNATIONAL FALLS 89,189 3.12% 54.77%

NC0003298 Intl Paper Co Riegelwood Ml Riegelwood 76,947 2.69% 57.46%

NC0000272 Blue Rdg Paper Products Inc Ca Canton 71,337 2.49% 59.95%

WI0003379 WAUSAU MOSINEE PAPER CORP BROKAW 61,853 2.16% 62.11%

WI0002810 PACKAGING CORP OF AMERICA TOMAHAWK 58,365 2.04% 64.15%

OH0004481 MW CUSTOM PAPERS LLC CHILLICOTHE 56,782 1.98% 66.14%

OR0000442 WEYERHAEUSER CO ALBANY 50,589 1.77% 67.90%

WI0000698 STORA ENSO NORTH AMERICA KIMBE KIMBERLY 49,962 1.75% 69.65%

AL0000817 MEADWESTVACO COATED BOARD INC COTTONTON 49,665 1.74% 71.39%

SC0001015 BOWATER INC/ COATED PAPER DIV Catawba 47,370 1.66% 73.04%

NC0000752 Intl Paper Co Roanoke Rpds Ml Roanoke Rapids 45,559 1.59% 74.63%

VA0003115 Smurfit Stone Container Corpor West Point 43,200 1.51% 76.14%

MI0042170 INT PAPER CO QUINNESEC MILL NORWAY 40,830 1.43% 77.57%

NC0003191 Weyerhaeuser Co New Bern Ml New Bern 36,507 1.28% 78.85%

FL0001104 JEFFERSON SMURFIT FERNANDINA FERNANDINA BEACH 36,438 1.27% 80.12%

MD0021687 UPPER POTOMAC RIVER COMMISSION WESTERNPORT 35,640 1.25% 81.37%

AL0025968 ALABAMA RIVER PULP CLAIBORNE 34,938 1.22% 82.59%

WI0026042 WEYERHAEUSER COMPANY ROTHSCHILD 32,499 1.14% 83.72%

WI0000990 APPLETON PAPERS INC APPLETON COMBINED LOCKS 32,452 1.13% 84.86%

OH0004235 STONE CONTAINER CORPORATION COSHOCTON 32,155 1.12% 85.98%

WI0037991 STORA ENSO NORTH AMERICA WATER WISCONSIN RAPIDS 26,891 0.94% 86.92%

WI0000825 INTERNATIONAL PAPER KAUKAUNA KAUKAUNA 24,269 0.85% 87.77%

MI0006122 STONE CONTAINER ONTONAGON 23,985 0.84% 88.61%

TN0001643 WEYERHAEUSER COMPANY KINGSPORT SHAKER CHANDRASEKARAN 23,880 0.83% 89.44%

FL0000400 STONE CONTAINER CORPORATION JACKSONVILLE 23,375 0.82% 90.26%

WI0003468 STORA ENSO NORTH AMERICA WRC STEVENS POINT 20,748 0.73% 90.98%

MI0000027 MEADWESTVACO ESCANABA PAPER CO ESCANABA 20,658 0.72% 91.71%

WI0003026 RHINELANDER PAPER CO RHINELANDER 16,602 0.58% 92.29%

NH0001562 WAUSAU PAPERS OF NH, INC. GROVETON 16,082 0.56% 92.85%

OR0000515 WEYERHAEUSER CO SPRINGFIELD 15,865 0.55% 93.40%

OH0105228 BAY WEST DIVISION MIDDLETOWN 15,402 0.54% 93.94%

WI0000752 STORA ENSO NORTH AMERICA NIAGA NIAGARA 14,245 0.50% 94.44%

MI0003824 MENASHA PACKAGING CO OTSEGO 13,460 0.47% 94.91%

NH0000655 FRASER PAPER N. H. LLC BERLIN 12,048 0.42% 95.33%

WI0003212 FRASER PAPERS INC PARK FALLS PARK FALLS 10,598 0.37% 95.70%

AL0003018 IP PRINTING PAPERS DIV RIVERDA SELMA 10,571 0.37% 96.07%

NY0004413 TICONDEROGA MILL TICONDEROGA 10,080 0.35% 96.42%

MT0000035 STONE CONTAINER CORP MISSOULA 8,760 0.31% 96.73%

OR0033405 FORT JAMES OPERATING CO HALSEY 8,119 0.28% 97.01%

MI0001171 PCA FILER CITY MILL FILER CITY 7,986 0.28% 97.29%

WI0037389 SCA TISSUE NORTH AMERICA LLC MENASHA 7,448 0.26% 97.55%

MI0003166 MANISTIQUE PAPERS INC MANISTIQUE 7,059 0.25% 97.80%

WI0003671 WAUSAU MOSINEE PAPER CORP MOSINEE 6,778 0.24% 98.04%

WI0001121 P H GLATFELTER CO BERGSTROM PA NEENAH 6,127 0.21% 98.25%

MI0053601 GREAT LAKES PULP & FIBRE MENOMINEE 5,601 0.20% 98.45%

NC0000078 Ecusta Business Dev Cntr LLC Pisgah Forest 5,351 0.19% 98.63%

PA0008869 PH GLATFELTER CO SPRING GROVE 5,245 0.18% 98.82%

WI0003077 CASCADES TISSUE GROUP WISC INC EAU CLAIRE 4,637 0.16% 98.98%

WI0003204 CITYFOREST CORPORATION LADYSMITH 3,999 0.14% 99.12%

MA0000671 CRANE & CO INC W W T P DALTON 2,474 0.09% 99.20%

PA0012815 SONOCO PRODUCTS COMPANY DOWNINGTOWN 2,458 0.09% 99.29%

NC0005321 BUCKEYE LUMBERTON, INC. LUMBERTON 2,375 0.08% 99.37%

WI0003611 KIMBERLY CLARK NEENAH PAPER STEVENS POINT 2,169 0.08% 99.45%

MA0001716 MEAD CORP  LAUREL MILL SOUTH LEE 2,065 0.07% 99.52%

WI0037842 KIMBERLY CLARK CORP NEENAH PAP NEENAH 1,965 0.07% 99.59%

FL0000892 JEFFERSON SMURFIT CORPORATION JACKSONVILLE 1,693 0.06% 99.65%

MA0005371 SCHWEITZER MAUDUIT, INT'L INC. LEE 1,370 0.05% 99.70%

MI0000060 MENOMINEE PAPER CO MENOMINEE 1,224 0.04% 99.74%

OH0009377 APPLETON PAPERS INC. WEST CARROLLTON 1,144 0.04% 99.78%

NY0000515 FELIX SCHOELLER TECH PAPERS PULASKI 774 0.03% 99.81%

MI0003093 FRENCH PAPER CO NILES 763 0.03% 99.83%

MA0000469 SEAMAN PAPER CO OF MASS INC OTTER RIVER 728 0.03% 99.86%

WI0001341 LITTLE RAPDIS CORP SHAWANO SHAWANO 695 0.02% 99.88%

AL0002780 INTERNATIONAL PAPER CO MOBILE MOBILE 642 0.02% 99.91%

MI0002160 E B EDDY PAPER INC PORT HURON 570 0.02% 99.92%

MN0001422 MISSOTA PAPER CO LLC BRAINERD 468 0.02% 99.94%

WI0000680 CELLU TISSUE NEENAH NEENAH 362 0.01% 99.95%

OH0000400 IVEX OF OHIO, INC. CHAGRIN FALLS 307 0.01% 99.96%

WI0000531 OCONTO FALLS TISSUE INC OCONTO FALLS 209 0.01% 99.97%

CT0003212 KIMBERLY CLARK CORPORATION NEW MILFORD 201 0.01% 99.98%

WI0001473 INTERNATIONAL PAPER DEPERE DE PERE 164 0.01% 99.98%

WI0000540 KIMBERLY CLARK CORP MARINETTE MARINETTE 132 0.00% 99.99%

AL0002801 KIMBERLY CLARK CORPORATION MOBILE 123 0.00% 99.99%

MA0001848 MEAD CORP  WILLOW MILL SOUTH LEE 116 0.00% 100.00%

NY0002755 OMNIAFILTRA  BEAVER FALLS BEAVER FALLS 36 0.00% 100.00%

AR0000558 INTERNATIONAL PAPER CO CAMDEN CAMDEN 16 0.00% 100.00%

NY0002372 LYONSDALE DIVISION LYONSDALE 12 0.00% 100.00%

Total Pulp and Paper Phosphorus Load 2,861,224 Phosphate Manufacturing Facilities Reporting Discharges of Phosphorus Compounds to PCS for 2002 NPID Name City Total Facility Phosphorus Load % of Total Phosphorus Load for Category Cummulative % of Total Phosphorus Load for Category LA0004847 IMC PHOSPHATES CO  UNCLE SAM UNCLE SAM 1,671,960 66.07% 66.07% anomaly  loads deleted FL0000523 CF INDUSTRIES  BARTOW PHOS. BARTOW 213,877 8.45% 74.52%

LA0003638 IMC PHOSPHATES CO  TAFT HAHNVILLE 194,340 7.68% 82.20%

FL0000752 GREEN BAY CHEMICAL COMPLEX BARTOW 125,941 4.98% 87.18%

FL0036421 IMC AGRICO CO  NEW WALES CHEM MULBERRY 110,669 4.37% 91.55%

FL0000761 RIVERVIEW CHEMICAL COMPLEX RIVERVIEW 86,974 3.44% 94.99%

NC0003255 PCS Phosphate Co Inc PCS Phosp Aurora 41,214 1.63% 96.61%

FL0001961 US AGRI CHEMICALS BARTOW PLANT BARTOW 38,865 1.54% 98.15%

TX0007285 AGRIFOS FERTILIZER, INC. PASADENA 31,563 1.25% 99.40%

FL0001589 BARTOW PHOSPHATE COMPLEX BARTOW 11,653 0.46% 99.86%

FL0030139 IMC AGRICO CO  NICHOLS CHEM MULBERRY 3,309 0.13% 99.99%

FL0000078 CF INDUSTRIES, PLANT CITY PLANT CITY 286 0.01% 100.00%

Total Phosphate Manufacturing Phosphorus Load 2,530,652 Mineral Mining and Processing Facilities Reporting Discharges of Phosphorus Compounds to PCS for 2002 NPID Name City Total Facility Phosphorus Load % of Total Phosphorus Load for Category Cummulative % of Total Phosphorus Load for Category FL0000655 PCS PHOSPHATE WHITE SPRINGS WHITE SPRINGS 888,860 43.94% 43.94%

FL0036226 PCS PHOSPAHTE WHITE SPRINGS WHITE SPRINGS 615,988 30.45% 74.39%

FL0000353 IMC AGRICO CO  PAYNE CK MINE MULBERRY 127,001 6.28% 80.67%

FL0000230 IMC AGRICO CO  NORALYN/ PHO. MULBERRY 105,390 5.21% 85.87%

FL0001902 US AGRI CHEMICALS FT MEADE FORT MEADE 96,453 4.77% 90.64%

FL0027600 IMC AGRICO CO  FT GREEN MINE MULBERRY 46,724 2.31% 92.95%

FL0036412 IMC AGRICO CO  FOUR CORNERS MULBERRY 29,557 1.46% 94.41%

FL0033294 HOOKERS PRAIRIE MINE BARTOW 24,466 1.21% 95.62%

FL0000256 IMC AGRICO CO  KINGSFORD MULBERRY 21,992 1.09% 96.71%

FL0001198 FORT MEADE MINE FT MEADE 16,582 0.82% 97.53%

FL0037958 SOUTH FORT MEADE MINE NICHOLS 12,835 0.63% 98.16%

FL0040177 CF INDUSTRIES  HARDEE COMPLEX WAUCHULA 11,028 0.55% 98.71%

FL0000311 AGRIFOS L. L. C.  NICHOLS MINE NICHOLS 8,568 0.42% 99.13%

FL0035271 C F INDUSTRIES  HARDEE WAUCHULA 5,285 0.26% 99.39%

FL0032590 IMC AGRICO CO  HOPEWELL MULBERRY 4,587 0.23% 99.62%

FL0033332 IMC AGRICO CO  LONESOME MULBERRY 3,499 0.17% 99.79%

FL0000264 IMC AGRICO CO  PORT SUTTON MULBERRY 2,619 0.13% 99.92%

FL0032522 WINGATE CREEK MINE MYAKKA CITY 1,556 0.08% 100.00%

Total Mineral Mining Phosphorus Load 2,022,989 Steam Electric Power Facilities Reporting Discharges of Phosphorus Compounds to PCS for 2002 NPID Name City Total Facility Phosphoru s Load % of Total Phosphorus Load for Category Cummulative % of Total Phosphorus Load for Category VA0004090 Dominion Virginia Power  Surr Surry 370,939 20.94% 20.94%

AL0002879 AL POWER CO BARRY STEAM PLT MOBILE 357,506 20.18% 41.13%

VA0004146 Dominion Virginia Power  Ches Chester 230,937 13.04% 54.17%

VA0004103 Dominion  Yorktown Yorktown 187,604 10.59% 64.76%

NC0003433 Prog Enrg Carolinas Inc Cpe Fe Moncure 147,551 8.33% 73.09%

NC0003425 Prog Enrg Carolinas Inc Roxbor Roxboro 116,399 6.57% 79.66%

VA0004081 Dominion Virginia Power  Ches Chesapeake 112,049 6.33% 85.99%

MI0042668 MIDLAND COGENERATION VENTURE MIDLAND 62,875 3.55% 89.54%

OH0063461 CLEVELAND ELECTRIC ILLUM. CO PERRY 26,540 1.50% 91.04%

NC0039586 Prog Enrg Carolinas Inc Shearo New Hill 20,492 1.16% 92.19%

AL0002909 AL POWER CO GORGAS STEAM PLT PARRISH 18,587 1.05% 93.24%

MO0001961 SPRINGFIELD, JAMES RIV PP SPRINGFIELD 18,568 1.05% 94.29%

HI0000094 MAUI ELECTRIC CO LTD KAHULUI 16,618 0.94% 95.23%

WI0043583 WE ENERGIES PLEASANT PRAIRIE PLEASANT PRAIRIE 12,933 0.73% 95.96%

OK0035149 GRAND RIVER DAM AUTH CHOUTEAU CHOUTEAU 9,868 0.56% 96.52%

HI0000353 KAUAI ISLAND UTILITY COOP. ELEELE 7,898 0.45% 96.96%

AL0003140 AL POWER CO E C GASTON STM PL WILSONVILLE 6,834 0.39% 97.35%

MI0038105 WYANDOTTE ELECTRIC PLANT & WFP WYANDOTTE 6,786 0.38% 97.73%

NC0005088 Duke Enrg Corp Cliffside Stm S Cliffside 5,751 0.32% 98.06%

HI0000191 HILO COAST POWER CO 5,015 0.28% 98.34%

FL0036498 SEMINOLE ELEC SEMINOLE STEAM PALATKA 3,977 0.22% 98.56%

AL0003875 TVA WIDOWS CREEK FOSSIL PLANT STEVENSON 3,411 0.19% 98.76%

OK0034380 PUBLIC SERVICE CO OF OKLA  NE OOLOGAH 2,859 0.16% 98.92%

AL0027146 AL POWER CO MILLER STEAM PLT QUINTON 2,794 0.16% 99.08%

DE0050580 DELMARVA P & L INDIAN RIVER PO MILLSBORO 2,016 0.11% 99.19%

WI0001589 WI POWER & LIGHT EDGEWATER GEN SHEBOYGAN 2,011 0.11% 99.30%

AL0003867 TVA COLBERT STEAM PLANT TUSCUMBIA 1,779 0.10% 99.40%

LA0062600 CLECO UTI. DOLET HILLS PLT PINEVILLE 1,221 0.07% 99.47%

CO0001091 PUBLIC SERVICE CO. OF COLORADO DENVER 1,202 0.07% 99.54%

FL0030988 FL PWR & LT MARTIN CNTY STEAM INDIANTOWN 1,128 0.06% 99.60%

DC0000094 PEPCO POTOMAC ELECTRIC CO. WASHINGTON 751 0.04% 99.65%

AR0000493 ENTERGY HARVEY COUCH STEAM ELE STAMPS 736 0.04% 99.69%

NC0004979 Duke Enrg Corp Plt Allen Stm S Belmont 703 0.04% 99.73%

NC0004961 Duke Enrg Corp Riverbend Stm S Mount Holly 665 0.04% 99.77%

SC0004278 DUKE ENERGY/ CATAWBA NUCLEAR Newport 549 0.03% 99.80%

CO0001104 PUBLIC SERVICE CO. OF COLO. DENVER 536 0.03% 99.83%

HI0000264 HAWAII ELECTRIC LIGHT CO INC HILO 512 0.03% 99.86%

NC0003468 Duke Enrg Corp Dan Riv Stm Sta Eden 353 0.02% 99.88%

NC0004774 Duke Energy Corp Buck Stm Sta Salisbury 313 0.02% 99.89%

CO0001139 PUBLIC SERVICE COMPANY OF COLO DENVER 212 0.01% 99.91%

MN0001007 MINNESOTA POWER/ WISC PUB POWER COHASSET 208 0.01% 99.92%

NC0004987 Duke Enrg Corp Marshall Stm St Terrell 194 0.01% 99.93%

WI0040223 DAIRYLAND POWER COOP ALMA 6 MA ALMA 181 0.01% 99.94%

TX0003565 LON C. HILL LP CORPUS CHRISTI 180 0.01% 99.95%

FL0000680 ORLANDO UTL COM INDIAN RV STM TITUSVILLE 180 0.01% 99.96%

NC0000396 Prog Enrg Carolinas Inc Ashevi Arden 153 0.01% 99.97%

NC0024406 Duke Enrg Corp Belews Crk Stm Walnut Cove 121 0.01% 99.97%

IL0000124 AMEREN CIPS  GRAND TOWER GRAND TOWER 105 0.01% 99.98%

PA0008281 PPL BRUNNER ISLAND LLC YORK HAVEN 97 0.01% 99.99%

PA0025615 FIRST ENERGY NUCLEAR OPERATING SHIPPINGPORT 83 0.00% 99.99%

OK0044083 KIOWA POWER PARTNERS,( KPP) KIA KIOWA 77 0.00% 99.99%

MA0004731 EXELON NEW BOSTON LLC SOUTH BOSTON 52 0.00% 100.00%

CT0003760 PSEG POWER CONNECTICUT LLC NEW HAVEN 14 0.00% 100.00%

PA0009920 AMERGEN ENERGY CO LLC  THREE MIDDLETOWN 8 0.00% 100.00%

NY0004472 INDIAN POINT STATION # 1 & # 2 BUCHANAN 7 0.00% 100.00%

PA0009733 EXELON GENERATION CO LLC  PEA 6 0.00% 100.00%

PA0005011 RELIANT ENERGY NORTHEAST MGMT NEW FLORENCE 2 0.00% 100.00%

Total Steam Electric Phosphorus Load 1,771,149 OCPSF Facilities Reporting Discharges of Phosphorus Compounds to PCS for 2002 NPID Name City Total Facility Phosphoru s Load % of Total Phosphorus Load for Category Cummulative %

of Total Phosphorus Load for Category NJ0005100 E I DU PONT DE NEMOURS DEEPWATER 275,647 26.53% 26.53%

AL0003093 CIBA SPECIALTY CHEMICALS CORP MCINTOSH 158,670 15.27% 41.80%

WV0002496 RIPPLEWOOD PHOSPHORUS U. S. LLC GALLIPOLIS FERRY 112,650 10.84% 52.65%

WV0000400 GREAT LAKES CHEMICAL CORPORATI NITRO 86,272 8.30% 60.95%

VA0005291 Honeywell International Incorp Hopewell 56,294 5.42% 66.37%

NH0000591 HAMPSHIRE CHEMICAL CORPORATION NASHUA 46,657 4.49% 70.86%

AL0000108 BP AMOCO CHEMICAL CO DECATUR 45,814 4.41% 75.27%

AL0003026 ACORDIS CELLULOSIC FIBERS INC AXIS 23,400 2.25% 77.52%

VA0005312 Honeywell Nylon LLC  Chesterf Chester 20,242 1.95% 79.47%

WV0005169 BAYER MATERIALSCIENCE, LLC NEW MARTINSVILLE 18,574 1.79% 81.26%

NC0000663 DAK Americas LLC Cpe Fear Site Wilmington 17,670 1.70% 82.96%

NC0001112 Arteva Specialities SARL dba K Wilmington 15,262 1.47% 84.43%

LA0104400 CIBA SPECIALTY CHEMICALS CORP ST. GABRIEL 14,460 1.39% 85.82%

MI0000868 DOW CHEM MIDLAND MIDLAND 13,830 1.33% 87.15%

CT0000086 CYTEC INDUSTRIES INC. WALLINGFORD 11,635 1.12% 88.27%

WV0000094 GE SILICONES LLC FRIENDLY 9,973 0.96% 89.23%

LA0005347 LYONDELL CHEMICAL LAKE CHARLES 9,630 0.93% 90.16%

OH0002615 PCS NITROGEN OHIO, LP LIMA OHIO 9,501 0.91% 91.07%

PA0070505 GEO SPECIALTY CHEMICALS INC ALLENTOWN 8,460 0.81% 91.89%

SC0002798 INVISTA S. A. R. L./ SPARTANBURG Spartanburg 8,390 0.81% 92.70%

VA0004669 E I du Pont de Nemours and Com Richmond 7,205 0.69% 93.39%

FL0002488 SOLUTIA INC. GONZALEZ 6,690 0.64% 94.03%

NY0007072 G E PLASTICS  SELKIRK OPER SELKIRK 6,003 0.58% 94.61%

RI0000132 CLARIANT CORPORATION COVENTRY 5,216 0.50% 95.11%

TX0002933 DOW CHEMICAL COMPANY, ( THE) LA PORTE 5,049 0.49% 95.60%

FL0002313 AIR PROD & CHEM ESCAM PENSACOL PACE 4,671 0.45% 96.05%

LA0005754 SHELL CHEM GEISMAR GEISMAR 4,147 0.40% 96.45%

NC0003573 E I DuPont de Nemours & Co Dup Fayetteville 4,090 0.39% 96.84%

MN0001449 3M COTTAGE GROVE COTTAGE GROVE 3,534 0.34% 97.18%

WV0004740 CROMPTON CORPORATION MORGANTOWN 3,426 0.33% 97.51%

AL0000205 3M CO DECATUR PLANT DECATUR 2,784 0.27% 97.78%

NC0004375 Clariant Corp Mt Holly E MHE F Charlotte 2,730 0.26% 98.04%

NY0001406 EVANS CHEMETICS WATERLOO 2,337 0.22% 98.27%

NC0005274 Yorkshire Americas Inc Yorkshi Lowell 2,336 0.22% 98.49%

NC0000299 BASF CORPORATION  ENKA PLANT ENKA 2,334 0.22% 98.72%

NC0003760 Unifi Kinston LLC Kinston 2,050 0.20% 98.91%

RI0000043 BRADFORD DYEING ASSOC., INC. BRADFORD 1,876 0.18% 99.09%

NY0068225 ATOCHEM NA ORGANIC GENESEO 1,290 0.12% 99.22%

MI0000761 FLINT INK CDR HOLLAND HOLLAND 979 0.09% 99.31%

GA0001708 GEO SPECIALTY CHEMICALS CEDARTOWN 923 0.09% 99.40%

WV0022047 CROMPTON CORPORATION Morgantown 874 0.08% 99.49%

AL0064351 DAIKIN AMERICA INC DECATUR 777 0.07% 99.56%

NC0000892 Dynea US A Inc Moncure 760 0.07% 99.63%

TX0089567 HAMPSHIRE CHEMICAL COPORATION DEER PARK 750 0.07% 99.71%

LA0005762 SHELL CHEMICAL LP NORCO 720 0.07% 99.78%

AL0042447 ATOFINA CHEMICALS INC AXIS 511 0.05% 99.82%

TX0106721 VALERO REFINING TEXAS, L. P. MORGAN'S POINT 418 0.04% 99.86%

TX0005592 HUNTSMAN PETROCHEMICAL CORP. SHOOT, MONTGOMERY CO. 316 0.03% 99.89%

NC0004952 CNA Holdings Inc Ticona Fac Shelby 277 0.03% 99.92%

PA0000507 EASTMAN CHEMICAL RESINS INC WEST ELIZABETH 266 0.03% 99.95%

NC0001899 Honeywell Intl Inc Moncure NC Moncure 187 0.02% 99.97%

OH0006769 OCCIDENTAL CHEMICAL KENTON 180 0.02% 99.98%

AL0026921 EASTMAN RESINS INC MOUNDVILLE MOUNDVILLE 134 0.01% 100.00%

NJ0031445 FIRMENICH INCORPORATED PLAINSBORO 20 0.00% 100.00%

MI0026034 WACKER CHEM CORP ADRIAN 14 0.00% 100.00%

SC0038229 NATIONAL STARCH & CHEMICAL CO Enoree 12 0.00% 100.00%

FL0029653 AOC, LLC LAKELAND 2 0.00% 100.00%

Total OCPSF Phosphorus Load 1,038,920 Meat and Poultry Processing Facilities Reporting Discharges of Phosphorus Compounds to PCS for 2002 NPID Name City Total Facility Phosphorus Load % of Total Phosphorus Load for Category Cummulative % of Total Phosphorus Load for Category NC0078344 Smithfield Packing Co Inc Tarh Tar Heel 292,413 31.57% 31.57%

AL0003697 PILGRIMS PRIDE CORP ENTERPRISE 111,645 12.05% 43.62%

KS0000817 TYSON FRESHMEAT INC EMPORIA EMPORIA 110,976 11.98% 55.60%

MN0031178 WORTHINGTON INDUSTRIAL WORTHINGTON 108,255 11.69% 67.28%

UT0000281 MILLER E A, INC HYRUM 80,007 8.64% 75.92%

OK0038849 HEAVENER UA INDUSTRIAL PARK HEAVENER 55,292 5.97% 81.89%

AL0040843 AMERICAN PROTEINS HANCEVILLE HANCEVILLE 49,127 5.30% 87.19%

WV0005495 PILGRIM'S PRIDE CORPORATION MOOREFIELD 47,346 5.11% 92.30%

AL0001449 TYSON FOODS BLOUNTSVILLE BLOUNTSVILLE 45,949 4.96% 97.27%

VA0003808 Perdue Farms Incorporated  Ac Accomac 5,947 0.64% 97.91%

DE0000469 PERDUE  GEORGETOWN GEORGETOWN 4,915 0.53% 98.44%

WV0047236 PILGRIM'S PRIDE CORPORATION MOOREFIELD 4,841 0.52% 98.96%

SC0000795 GOLD KIST POULTRY PROCESSING Sumter 3,265 0.35% 99.31%

VA0003867 Omega Protein  Reedville Reedville 2,242 0.24% 99.55%

AL0003395 GOLD KIST POULTRY TRUSSVILLE TRUSSVILLE 2,014 0.22% 99.77%

MI0037451 BIL MAR FOODS ZEELAND 739 0.08% 99.85%

DE0000299 ALLEN FAMILY FOODS HARBESON 729 0.08% 99.93%

MD0002071 TYSON FOODS INC. BERLIN, WORCESTER CO 504 0.05% 99.98%

MD0000965 PERDUE FARMS INC./ SHOWELL SHOWELL 140 0.02% 100.00%

Total Meat and Poultry Phosphorus Load 926,344