This guideline provides an excellent simulation of chronic exposure for chemicals that are present in the environment for long periods of time, either because of their refractory nature or application in the environment. It measures the potential for bioaccumulation of the test substance in tissues and its deposition into eggs and detects toxicity and reproductive injury from long term exposure. The harmonized guideline provides statistical information and allows for application of regression analysis if the number of treatment levels and the data are adequate.

However, the 20 week continuous dietary exposure period is not realistic for most contemporary chemicals and pesticide exposure scenarios. The exposure protocol also does not account for the rapidity with which dietary exposure of chemicals can affect reproductive performance in birds and fails to trigger a test for substances that pose a risk to reproductive success from short term exposure. In addition, the length of laying period appears to reduce statistical power, because it approaches the biological limits of some birds. It thereby introduces high variability within groups, because some birds remain in production while others no longer lay eggs.

A major weakness of the OPPTS test guideline that has become apparent as past data have been reviewed is that the statistical power of the test is low for some endpoints, making it difficult to detect effects that could be biologically significant. Battelle Draft 118 April 23, 2003 Also, reliance on using estimated environmental concentrations to determine exposure concentrations, although sound from a realism perspective, is problematic when significant differences are detected in all dose groups or in none. If no effects are observed, it cannot be determined whether the dietary concentrations are truly below those causing reproductive deficits or whether effects could not be detected because of inadequate test design. There is also no information on how close the tested concentrations are to those that cause effects. In contrast, if effects are observed at all dietary concentrations, no information is obtained on the impact of lower concentrations on reproductive performance. Because of the usually limited concentration selection, there is little predictive capability in protocol design that would aid in the assessment of potential risk of a chemical for a new use at higher or lower concentrations than those originally tested.

The guideline does not evaluate exposures to life stages other than the adult and egg. Therefore, many potential effects on reproduction may not be detected. With the exception of eggshell thickness, most of the endpoints measured are not indicators of endocrine disruption, and although the survivability of the P1 offspring is measured, their reproductive capacity is not. As a one generation test, there is no evaluation of chemicals on the F2 progeny.

11.1.2 OECD 206 The OECD one generation test is similar to OPPTS 850.2300 and shares many of the same strengths and weaknesses. However, it differs in three major ways from the OPPTS protocol. First, the Japanese quail is an acceptable species in the OECD 206 guideline. Use of the Japanese quail with its extended breeding period could reduce the variability in egg production and related parameters that is encountered in the OPPTS protocol, because the bobwhite and mallards approach the end of the reproductive limits after 10 weeks of egg laying. Secondly, the OECD protocol recommends that Japanese quail be proven breeders before they are used in the test. The test begins with dietary exposure of the birds under short day conditions ( non egg laying) for 8 weeks prior to the initiation of a long day photoperiod to bring the birds into breeding condition. Proven breeders are birds that were reproductively successful previously and that start the test approaching their second breeding season. Using firs year breeders in a test in which the treatment is initiated prior to onset of breeding, as in the OPPTS guideline, does not allow for removing infertile or incompatible pairs, because the infertility could be a result of treatment. Use of the proven breeders reduces the variability and increase the power of the test. Thirdly, the OECD protocol establishes dietary treatment concentrations based on a range finding test that does not necessarily incorporate an estimated environmental concentration such that the concentrations tested are based on toxic response ( ½ LC10). The test is therefore less likely to produce the situation described above for the OPPTS guideline, where the lack of effects in all treatment groups cannot be attributed to concentrations truly below those causing reproductive effects, because the design of the test could have been inadequate to detect effects. Battelle Draft 119 April 23, 2003 11.1.3 ASTME1062 86 The ASTM guideline was designed to be flexible in its approach to screening for reproductive effects. It could be used to duplicate the OPPTS 850.2300 test design or to create a design that attempts to overcome some of the weaknesses of the both the OPPTS and OECD 206 guidelines. Design options were provided in varying detail for testing nonpersistent chemicals, limiting collection of egg production to within the biological capacity of the species, assuring that the power of the test was adequate to detect effects, and selecting treatment concentrations linked to toxic response rather than field concentration.

Unlike the other one generation studies, the ASTM guideline suggested that the exposure period for nonpersistent test substances may be shortened and dietary concentrations decreased to simulate declines under field conditions. However, the recommendations were vague, and no discussion or criteria for selecting one of the optional exposure scenarios were provided. Dietary exposure prior to the onset of egg production could be less than 10 weeks, or for some chemicals, exposure can be initiated during egg laying. Although the potential benefit of using pre exposure data as covariates for birds is increased power; the disadvantage is the inability to determine whether the chemical affected the onset of egg laying.

Whereas the OPPTS 850.2300and OECD 206 guidelines recommend a post egg laying exposure and an egg collection period of 10 weeks, the ASTM protocol recommended an egg collection period for the bobwhite and mallard equivalent to laying two clutches, or 25 eggs. This egg laying period is within the biological limits of these species and could reduce one source of variability that is unrelated to chemical treatment. However, the variability of proportional measurements based on the numbers of eggs laid could increase as a result of the reduced numbers of eggs collected. Also, the shortened egg collection period, could be too short to detect effects that are delayed or increase in severity during treatment. For example, effects such as those on early germ cells in the Japanese quail would not be manifested until about 3 weeks after exposure is initiated. If birds were exposed prior to egg laying, and the onset of egg laying were delayed, the resulting delay in peak egg production would be overlooked by the shortened egg collection period, and an overestimate of the severity of impact could be inferred.

The ASTM protocol also provides a statistical means for estimating the number of replicates needed to assure sufficient power to detect selected effects. Although useful and made readily calculable by means of an appended table, the information on the coefficients of variation for various endpoints, in particular endocrine endpoints, in the species or strain being used may not be available to the investigator.

The remaining strength of the ASTM guideline is the use of toxicity based information to establish the treatment concentrations so as to avoid the shortcomings of using an expected field concentration criteria discussed in Section 11.1.1. The disadvantages of using toxicity based criteria is the need for a range finding test( s) to establish the appropriate dietary concentrations and the diminished usefulness of tissue and egg residues if the test concentrations are considerably different from the expected environmental concentrations. Battelle Draft 120 April 23, 2003 Other options of the ASTM protocol included the use of natural incubation and the potential to use behavioral endpoints and examine multigenerational effects. Little information is provided for these options.

11.1.4 OECD Revised Draft Proposal ( April 2000) for a New Test Guideline, Avian Reproduction Toxicity Test in the Japanese Quail or Northern Bobwhite The April 2000 revised draft proposal for a new test guideline, Avian Reproduction Toxicity Test in the Japanese Quail or Northern Bobwhite ( ARTT 2000), is similar to the optional exposure scenarios of the ASTM guideline in that it has a limited exposure period. To accommodate bioaccumulating substances that may require lengthy exposure periods to achieve steady state concentrations in the test subjects, both the OECD 206 and the OPPTS 850.2300 guidelines prescribe 8 to 10 week exposures prior to egg laying and a similar exposure period after egg laying has begun. Exposure in the ARTT 2000 guideline is limited to 6 weeks after egg production has been established, limiting the applicability of the guideline to nonbioaccumulating chemicals. However, contemporary chemicals are more likely to be nonpersistent which reduces the severity of this limitation.

The short exposure period of the ARTT 2000 guideline is a result of an effort to increase the statistical power to detect treatment effects. By using pairs of birds that are proven breeders, pre treatment differences in birds can be used to correct post treatment effect measurements and reduce the variability within treatment groups; thereby making it more likely that treatment differences will be detected. Also contributing to reduced variability in the test is the ability to remove unfertile and incompatible pairs prior to start of treatment. The disadvantage of this approach is the inability to detect effects on reproductive maturation.

Although the OECD 206 guideline also provides for a proven breeder exposure scenario for the Japanese quail, it is able to retain the advantage of increased power from using pre exposure data as covariates for birds while at the same time providing an extended exposure period of up 20 weeks by using birds approaching their second breeding season and reproductive data from the previous season. Increased cost, space utilization etc., is, of course, required to obtain the baseline data.

Although liver, spleen, and testes weights and descriptive records of abnormal behavior are required, this guideline lacks, as do the other one generation tests, reproductive evaluation of the P1 offspring or endpoints that effectively detect endocrine disruption.

11.2 Two Generation Life Cycle Test The two principal designs being considered for an avian two generation reproduction test are a proven breeder design, where reproduction is monitored pre exposure, and a pre egg laying exposure design, where effects on maturation are included. The ( EPA 1998) recommendations for extending the EPA OPPTS 850.2300 one generation avian reproduction test to a twogeneration guideline included a pre egg laying exposure regime for the P1 generation. A proposed two generation guideline ( OECD 1999) was developed based on these Battelle Draft 121 April 23, 2003 recommendations, but suggested a proven breeder design. Bennett et al. ( 2001) discussed the advantages and disadvantages of proven breeder and pre egg laying exposure protocols in detail.

11.2.1 Proven Breeder Design The proven breeder protocol increases statistical power by 1) eliminating pre egg laying exposure allowing nonlayers to be removed prior to treatment so that the confounding effects of nonbreeders are eliminated, 2) introducing a pretreatment period during peak egg laying, in which reproduction data are collected to be used as covariates, and 3) using a shorter egg laying period ( 6 weeks), so that birds are laying at a more constant rate throughout the entire exposure. The shorter exposure period is more consistent with the minimal persistence and bioaccumulation characteristics of contemporary chemicals. The exposure can be lengthened somewhat to accommodate longer lived substances, particularly if the Japanese quail is used. Japanese quail maintain a longer period of peak egg laying than the period suggested in the protocol which is based on the bobwhite. A major improvement in this design over that of the one generation protocols is the increased sensitivity of the test resulting from a more comprehensive evaluation of the P1 progeny and the addition of endocrine endpoints.

Although increased power to detect effects is obtained by this design, it comes at the sacrifice of information on maturation effects, such as delayed onset of egg laying. However, these endpoints can be measured during the maturation of the F1 generation. Proven breeders from a previous breeding cycle could also be used to reduce variability in a prebreeding exposure scenario. The retention of the same level of egg production and fertility over multiple breeding cycles in aging birds may be unlikely.

The statistical concerns that motivated the proven breeder design for the P1 generation cannot be eliminated in the F1 breeders, because they receive treatment throughout their life cycle. Therefore, because mortality is likely, the test is vulnerable to problems of decreased power to detect effects in the F1 reproduction measurements. Also, if delayed effects occurred, the 6 week period of data collection could be insufficient to detect the changes. Delayed onset of egg laying in the F1 would also result in a delay of peak egg production. Egg production may not otherwise be impaired, but could appear to be so under the short exposure period of this design.

Measurement of endocrine status is significantly enhanced in this two generation protocol. Endpoints include measures of steroid and thyroid hormones, maturation of hormone mediated secondary sexual characteristics, organ condition , and spermatid quality and number. The protocol is lacking somewhat in assessing endocrine impacts on F1 and F2 progeny. However, EDSTAC ( EPA 1998) focuses on endpoints that evaluate effects on the 14 day old chicks. Reproduction endpoints are similar to those of the one generation studies.

A major weakness of both two generation protocols is the reliance on detecting effects by comparison of means. There is potential for delayed effects in both the P1and F1 generations: that is, delayed manifestation of effects on spermatogonia for up to 3 weeks in Japanese quail and delayed recruitment of yolk to maturing oocytes in the P1 generation, and delayed onset and Battelle Draft 122 April 23, 2003 peak production of eggs in the F1. Therefore, a regression approach to analyzing the data would better define the level and pattern of toxicity. Animal numbers can be reduced, because the dependence on replication is diminished in regression statistics.

11.2.2 Pre Egg laying Exposure Design The pre egg laying protocol is similar to the proven breeder design, except the birds are paired and exposed to the dietary treatment prior to egg laying. Exposure prior to egg laying could impact developing systems that would not be vulnerable in the mature reproductive animal. Such exposures could cause precocial or delayed onset of egg laying that would not be detectable in a proven breeder design. Considerable loss of power has been demonstrated when nonproducing pairs cannot be removed from the test and pretreatment egg production cannot be used as covariates to reduce sources of nontreatment variation ( Springer and Collins 1999). It is possible that proven breeders approaching their second breeding season could be used so that exposure could begin prior to the onset of egg laying, thus obtaining both information on pre egg laying effects and the statistical benefit of reducing the confounding effects of nonbreeders. However, age effects would have to be taken into account, and the benefit of using pretreatment egg production data is still lost by this option.

Because much of the information obtained from a two generation reproduction toxicity test will be related to the P1 population, it is important that the reproductive homogeneity of the test population be assured. This is best attained by not only accounting for equivalent body condition ( body size, weight, and health) in the test groups, but also equivalent ability to produce and fertilize eggs. One of the major weaknesses of the pre egg laying design is that it cannot assure a homogeneous test population from which to detect changes due to chemical and endocrine challenge.

12.0 RECOMMENDED PROTOCOL AND ADDITIONAL DATA NEEDS 12.1 Preferred Test Species Of the few bird species available that breed successfully under laboratory conditions, the Japanese quail is the preferred test species, because it is an indeterminate egg layer that matures much more rapidly than other species. It has both a higher rate of egg production and a longer period at which peak production is maintained than the northern bobwhite. In addition, the reproductive physiology, endocrinology, and behavior of the species are better characterized than those of the bobwhite. Spermatogenesis is most fully described in the Japanese quail, among avian species; therefore, the minimum length of exposure required for germ cell effects to be manifested extragonadally can be calculated. The cycle of the seminiferous epithelium of the bobwhite has not been determined. Also, the unique cloacal gland of the male can be used as a measure of maturity and androgen disruption, as can the sexually dimorphic plumage of the species. The Japanese quail has been used in toxicity tests and appears to be of comparable sensitivity to environmental chemicals as the northern bobwhite, though a direct comparison of their relative sensitivity to substances that disrupt reproduction and endocrine function is only Battelle Draft 123 April 23, 2003 currently being assessed. Although there are problems such as strain characteristics and high sensitivity to inbreeding associated with the extensive domestication of Japanese quail, the advantages of using this species outweigh those of the less domesticated bobwhite.

12.2 Exposure Protocol Currently, there are insufficient data to determine the combination of exposure protocols for the P1 and F1 generations that is the most robust for documenting changes in ecologically important fitness endpoints, and that at the same time is the most effective in determining mechanism of action. Therefore, a side by side performance evaluation of the prebreeding and proven breeder exposure regimens, each one combined with a nontreated and a worst case, hatch throughegg laying F1 exposure scenario is recommended to evaluate the sensitivity and cost benefit of these protocols. The proven layer exposure has advantages, because removing infertile pairs provides for the endpoints to be assessed from an established and homogeneous fecundity in the P1 generation. In particular, the primary biological endpoint of the test, the number of F2 14 day old survivors per P1 generation pair per day, can be assessed. Likewise, exposing the P1 generation after the onset of egg laying avoids the complication of delaying maturation, thereby shifting the period of peak egg production in affected birds, in some cases beyond the exposure period. If reproduction is otherwise not affected, this asynchrony in production could result in misleading conclusions regarding egg production and associated endpoints, and greatly reduce the number of hatchlings available for assessing F1 survivorship and forming the F1 parental generation. There are also considerable statistical benefits in the proven breeder scenario, when endpoints are evaluated by comparisons of means to the control.

The advantages of the pre egg laying exposure design are the ability to detect affects that alter maturation ( e. g., onset of egg laying, foam production) and to have long enough exposure that near steady state concentrations in the tissues of treated birds will be attained during the exposure period and adequate assessment of impact achieved for the more persistent, bioaccumulating substances.

Exposure of the F1 from hatch through egg laying is recommended in semblance of a worst case exposure, because it allows the expression of effects on susceptible growth and developmental stages, in addition to effects manifested in the P1 generation. For substances expected to cause significant juvenile mortality, a subset should be exposed from hatch through egg laying, while another cohort is not exposed. The time of onset of egg laying, one of the more sensitive measures of endocrine disruption, can be detected under this exposure regimen and could minimize the need to detect altered maturation using a prebreeding exposure scenario in the P1 population. However, it is not known whether the previous in ovo exposure of the F1 chicks would confound the interpretation of the response compared with the response measured in P1 birds that lack in ovo exposure.

Data on the onset of sexual maturation in the P1 generation could be obtained from the current one generation reproduction toxicity tests ( OPPTS Guidelines 850.2300; OECD Guidelines 206) at little added cost. The one generation tests could also supply yolk residue data that would provide information on the length of exposure needed for maximum transfer of the test substance Battelle Draft 124 April 23, 2003 to the egg. Lastly, dose response data from the one generation tests would also greatly aid in selecting appropriate test concentrations for the multigeneration test.

12.3 Appropriateness of Reproductive Endpoints In general, the reproductive fitness endpoints of reproductive output, developmental adequacy, and appropriate behaviors, for example, described in both the one generation and two generation candidate protocols, provide useful data on the reproductive function of the mated pairs. However, because the male has opportunity for multiple copulations, egg fertility is not necessarily a sensitive indicator of impact on male fecundity. Assessment of the relative fertility of the male at the onset of test is needed in a proven layer exposure regimen to assure that the groups begin on test with equivalent reproductive capacity in males as well as females. An assay such as the sperm mobility test or sperm penetration of the perivitelline layer should be added as an inexpensive means of tracking gender specific changes in fertility.

Valuable endpoints for evaluating effects on reproduction and endocrine system function in adults that are described in the candidate two generation reproduction tests are ° onset of sexual maturation ( first egg, foam production) ° cloacal gland area ° male copulatory behavior ° plasma and fecal/ urate steroid hormones ° gross morphology and histology of specific organs, such as liver, spleen, gonads, brain, thyroid, and adrenals.

Some modification of these endpoints is recommended to reduce redundancy, increase the cost effectiveness of the test, and provide higher quality data. Both size and weight measurements of the organs are suggested in these protocols; however, size measurements of the organs provide little additional data at increased labor cost and are not recommended. Also, considerable timesaving will be realized during necropsy if the thyroid and adrenal glands are excised for histological examination rather than for organ weight. Removing and trimming these tissues for weight measurements is time consuming and damaging to the tissue. Better quality data are obtained from histological examination of these tissues. Histological examinations should only be conducted on organs from birds receiving the highest dietary concentration of the test substance and on controls. If chemical induced abnormalities are observed, the tissues from birds in the lower dose groups should be examined.

Other endpoints suggested by the candidate two generation protocols that are not useful at this time are spermatid counts and morphology, VTG, and several brain chemistry measures. Microscopic enumeration of spermatids and morphological abnormalities of sperm are timeconsuming to document and have been found to be relatively poor indicators of reproductive capability in male birds. A major effort in poultry research in recent years has been the development of more reliable assays of male condition based on measurements of sperm function, rather than semen quality. These assays are mainly based on measures of the interaction of sperm with the inner or outer perivitelline layer of the egg. They do not require Battelle Draft 125 April 23, 2003 special expertise or physically handling the bird to obtain a semen sample ( samples can be obtained from the same eggs as those used for egg quality tests) and are inexpensive to perform. Substitution of a perivitelline assay for the spermatid counts is recommended. It is not known at this time how useful VTG assays will be in birds, and only recently has an assay been reported that uses the necessary species specific antibodies for quail. If it is as sensitive of an endpoint as it has been shown to be in other oviparous animals, it could be a valuable inclusion in the guideline at a future date. Several brain chemistry endpoints, such as GnRH, catecholamine, aromatase, and vasotocin, which have been used to identify and investigate hormonally dimorphic areas of the avian brain, are histochemical techniques requiring considerable expertise, preparation, and computer image analysis. It should be noted that these endpoints are currently being adapted to more routine laboratory procedures and evaluated for their potential use as indicators of endocrine disruption. Few data are available in the literature on these endpoints, because they are only currently under testing. Researchers conducting this work report that GnRH appears to be relatively insensitive as an endpoint of endocrine disruption, but that preliminary data from dose response tests with a weak estrogenic compound indicate that catecholamines and vasotocin are promising, having application at all life stages and adaptability to routine laboratory procedures, such as RIA. These procedures are obviously terminal, requiring the sacrifice of the animal, and would therefore be applied to brain tissue gathered at adult necropsy and from the 14 day chicks.

EDSTAC ( EPA 1998) endpoint recommendations mainly focus on evaluation of the 14 day surviving chicks. Determining the genetic sex of the 14 day old survivors at hatch provides a good measure of in ovo disruption of endocrine systems. EDSTAC ( EPA 1998) then recommends selecting a subset of males and females from each group for gross and histological examination of gonadal tissue. The gonadal tissue of all males and all females in the high dose group and controls should be weighed and its external appearance described. Relative amount of cortex and medulla, and the development of oocytes should be histologically determined on a subset of males, as described by EDSTAC ( EPA 1998). Oviduct weight and differentiation should also be determined. However, to keep costs of the test within a reasonable range, these endpoints should be measured on a single cohort of hatchlings, preferably from the latter half of the exposure period, to assure maximum transfer of the test substance to the yolk. If the incidence of phenotypic change in the high dose group is above that found in the control group, the remaining treatment groups should be examined. Companion determination of circulating steroid concentrations is also a valuable endpoint suggested by EDSTAC ( EPA 1998). The committee also suggested the determination of organ weights, particularly the thyroid weight, for all chicks. As discussed above, thyroid weights are not recommended, because of the difficulty in removing this tissue without severely affecting the more informative histological examination of the tissue. The benefit of collecting organ weights on all chicks does not appear to warrant the cost involved and is not recommended. However, the wing and bone length measurements would provide an index of thyroid function. Although skeletal x ray would provide an additional measure of thyroid effects, it does so at high cost and also is not recommended. However, x ray could also be used to detect medullar bone formation in males and females in response to chemical challenge. A battery of behavioral tests is recommended by EDSTAC ( EPA 1998) for the 14 day old chicks. This endpoint has merit, though the composition of the Battelle Draft 126 April 23, 2003 test battery needs further investigation to refine protocols, validate sensitivity, and assure applicability to a broad range of chemicals.

12.4 Preferred Methods for Quantification of Biochemical Endpoints The sex hormones, corticosterone, and the thyroid hormones can be determined by RIA or ELISA methods. Commercial kits are available and are adaptable to use on birds and samples from various matrices. RIA methods are often more sensitive, but ELISA techniques, also highly sensitive, lack the additional cost and issues involved with working with radioisotopes. Because many of the hormones respond rapidly to stress, handling, and bleeding procedures, the preferred sampling method is from fecal/ urate samples, rather than from plasma. Fecal steroid sampling has been validated in a wide array of animals including birds, and evaluated under both laboratory and field conditions. Sampling feces will allow periodic sampling of hormone status rather than single point, terminal evaluations that can be misleading, particularly for thyroid hormones. Steroid hormones can also be sampled during egg laying, by this manner, without the danger of decreasing egg production or inducing body checks in eggs from handling stress of the hens. Because male Japanese quail usually must be removed from the hen several times during a week to prevent injury from aggressive behavior by either mate, monitoring of fecal steroids by sex can be accomplished in their separate home cages. Although the thyroid hormones have not been measured in feces, it is highly likely that this noninvasive method can be easily applied to T3 and T4. Use of fecal/ urate samples for hormone monitoring under the dosing regime of the two generation laboratory test will also provide a direct comparative measure for field collected samples.

Determination of genetic sex by DNA methods is preferred over the more lengthy and costly karyotyping techniques. Western Dot Blot or PCR methods are equally reliable; the dot blot technique is somewhat more rapid.

Several promising biochemical methods in development ( VTG, catecholamine, and vasotocin) are being adapted to RIA or ELISA techniques because of their superior sensitivity and ease of measurement. Again, additional convenience and some cost savings are attained when ELISA techniques are employed. Battelle Draft 127 April 23, 2003 12.5 Significant Data Gaps Several data gaps were found in the course of the review. Among these gaps is the lack of clear information on the transfer to and fate of xenobiotics in ovo. Chemical transfer to the egg has been variably described from tissue or dietary sources. The source of the in ovo concentrations of test substances has impact on decisions regarding exposure duration and interpretation of endpoint responses. Further study of estrogenic xenobiotics that require metabolic activation is needed to determine whether or not this occurs in the embryo, and if so, its relationship to the sensitive developmental period. Additional work is also needed to determine whether reduced levels of the 5" metabolites, through blockage of the reductase enzymes, are more likely to cause adverse effects than is reduction of the parent compound.

Because histopathological evaluations are observer based, the procedures for their use must be standardized to produce repeatable results that can be verified by different investigators. Avian histopathological evaluations in the context of toxicity assessments have had little formalization of technique, description, or morphometric analysis although there are standard practices and vocabulary in use by organizations such as the American Association of Avian Veterinarians and the College of Veterinary Pathology Little is known of the interactive effects of endocrine active substances. In particular, most test diets ( and vegetable oil carriers) contain variable amounts of the natural phytoestrogens and phytoandrogens. How these chemicals affect the bird's response to the test substance ( a suspected endocrine active compound) is unknown. Dietary treatments or changes to eliminate this potential interference will need to be investigated.

Significant genetic differences exist between strains of Japanese quail that are used in avian reproductive testing. It is not known whether these differences can have significant effects on the outcome and interpretation of the test. Further investigations into traits that are coselected with high body weight or high fecundity are needed. The feasibility and criteria for establishing and maintaining a random bred line from a natural source, such as UBC, or a standard random bred line with selected qualities for toxicity testing needs investigation.

If ANOVA methods continue to be applied to avian reproduction toxicity tests, a statistical approach for delayed effects must be investigated. For example, in a 6 week exposure period, only during the final 3 weeks of this period will the full effects of a test substance on fertility, embryo viability, hatching success, and sperm quantity and quality be observed because of the about 21 days needed for effects on spermatogonia to be expressed extragonadally. No effective statistical method has been identified for analyzing such a delayed treatment effect so far. Springer and Collins ( 1999) conducted simulation tests using an adaptation of the Roth step down trend test incorporating covariates for the last 3 weeks ( Weeks 8  10) of a standard bobwhite quail reproduction toxicity test. They found that using only the last 3 weeks of data can result in a decline in the power of the test to detect the number of chicks that hatched per number of eggs incubated, and the number of hatchlings that survived 14 days. Battelle Draft 128 April 23, 2003 Though seemingly a minor data gap, the lack of specific information on husbandry requirements of the Japanese quail that will result in consistent results in laboratory toxicity tests is important. As indicated in a comparative study of five laboratories using the same source of birds and test substances ( Schlatterer et al. 1993), a number of parameters differ significantly among laboratories ( e. g., number of eggs with cracks, food consumption, eggs laid, etc.), potentially resulting in different conclusions regarding the hazard a chemical poses. Species specific information needs to be developed for dealing with fear, social stress, injurious pecking , and other behavioral problems of Japanese quail in laboratory reproduction tests. These behaviors seriously harm the birds' welfare and productivity ( Jones and Hocking 1999). Much can be learned from anecdotal information and experience of flock curators, but it should be verified for the various growth and maturation stages of the quail in testing situations.

13.0 IMPLEMENTATION CONSIDERATIONS Pre validation considerations that are important to the development of the avian reproduction test include the following. Because there is not enough information available to determine the combination of the P1 and F1 exposure protocols that is the most advantageous for evaluating reproductive effects and determining mechanism of action, a direct performance comparison of the proven breeder and prebreeding exposure regimens combined with nontreatment and worstcase hatch through egg laying F1 exposure scenarios is needed for the selection of the appropriate exposure regimen.

Considering the sensitivity of the Japanese quail compared with that of the northern bobwhite, the effects of strain selection on test outcome should be determined prior to implementing the test protocol to verify the sensitivity of the test species and to minimize nontreatment variability across laboratories. Likewise, husbandry practices need review and standardization to reduce interlaboratory variability and to reduce behavioral problems of Japanese quail in laboratory reproduction tests.

Avian histopathological evaluations in the context of toxicity assessments have had little formalization of technique, description, or morphometric analysis. Because histopathological evaluations are observer based, the procedures for their use must be standardized to produce repeatable results that can be verified by different investigators.

If ANOVA methods continue to be applied to avian reproduction toxicity tests, a statistical approach for delayed effects should be investigated.

T4/ T3 are important indicators of thyroid function, but are limited in value when obtained from plasma samples because of their sensitivity to handling and bleeding, and because plasma fluctuation of these hormones render it difficult to document hypo or hyperthyroidism from a single sample. These hormones are excreted through the bile. Therefore, development of T4/ T3 assays in fecal/ urate samples could make the ability to monitor thyroid hormones noninvasively over time readily available. Battelle Draft 129 April 23, 2003 PCR methods for genetic sex determination need to be optimized for the Japanese quail.

The interactive effect of phytoestrogens in test diets needs investigation, and concentration limits for natural phytoestrogens in feed should be established relative to the potential impact of these compounds on test outcome.

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