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June 17 - 20 SAP Meeting Agenda

June 16, 2003

NOTE: ON FRIDAY, JUNE 20, 2003, THE FIFRA SAP WILL BE MEETING AT:
THE HOLIDAY INN NATIONAL AIRPORT HOTEL,
2650 JEFFERSON DAVIS HIGHWAY,
ARLINGTON, VA 22202.
703-684-7200

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
OPEN MEETING
JUNE 17 - 20, 2003
FIFRA SAP WEB SITE https://www.epa.gov/scipoly/sap/
OPP Docket Telephone: (703)305-5805
Docket Number: OPP-2003-0024

TUESDAY, JUNE 17, 2003
Crowne Plaza Hotel Washington - National Airport
1489 Jefferson Davis Highway
Arlington, VA 22202
703-310-8980

Potential Developmental Effects of Atrazine on Amphibians

WEDNESDAY, JUNE 18, 2003
Crowne Plaza Hotel Washington - National Airport
1489 Jefferson Davis Highway
Arlington, VA 22202
703-310-8980

Potential Developmental Effects of Atrazine on Amphibians

THURSDAY, JUNE 19, 2003
Crowne Plaza Hotel Washington - National Airport
1489 Jefferson Davis Highway
Arlington, VA 22202
703-310-8980

Potential Developmental Effects of Atrazine on Amphibians

In reviewing the available laboratory and field studies, the Agency used a number of criteria to evaluate individual investigations. Criteria such as experimental design, test protocols, and quality assurance information were used to ascertain the reliability of the generated data in terms of its ability to adequately assess a hypothesis that atrazine elicits developmental effects in amphibians, and if so, the nature and strength of associated dose-response relationships.

  1. Does the SAP have any comments and recommendations regarding the EPA's approach and criteria used to evaluate the studies?
  2. Given the evaluation criteria employed by the Agency, please comment on EPA's overall characterization of the currently available studies.
  3. Please comment on the availability, as of February 28, 2003, of additional, relevant studies in the open literature that were not addressed in the white paper.
    Since February 28, 2003, is the Panel aware of any studies that would be relevant?

Lead Discussant: Darcy Kelley, Ph.D.
Associate Discussants: Joel Coats, Ph.D. and Sherril Green, Ph.D.

In its evaluation of existing field studies, the Agency has concluded that these investigations are of limited value. The reasons include: (1) the high variability in environmental conditions and uncertainties in the pre-existing status and condition of field-collected animals, (2) the spatial and temporal aspects of atrazine exposure (i.e., spatial and temporal variability over the course of the studies and the extent to which such aspects of atrazine exposure were empirically measured or otherwise accounted for), and (3) the possible co-occurrence of additional chemical and/or non-chemical stressors.

  1. To the extent that the field studies appear to indicate that atrazine may not adversely affect development, please comment on EPA's conclusion that the body of data from field studies does not provide the means to ascertain whether the lack of a relationship between atrazine exposure and developmental effects is due to the absence of a causal relationship or limitation in study methodologies.

  2. To the extent that any field studies appear to indicate that atrazine may adversely affect development, please comment on EPA's conclusion that these field studies do not provide sufficient information to resolve the potential role of additional co-occurring stressors.

Lead Discussant: Carl Richards, Ph.D.
Associate Discussants: James Gibbs, Ph.D. and David Skelly, Ph.D.

In an evaluation of the existing laboratory-based studies, the Agency concluded that there was sufficient information to establish a hypothesis that atrazine could cause adverse gonadal developmental effects. However, due to different experimental designs and variability in the nature and extent of experimental conditions (e.g., level of excessive mortality, delayed development in untreated organisms, lack of response to positive controls) it was not possible to adequately assess the hypothesis that atrazine causes developmental effects. It was further concluded that the current body of information did not provide the means to characterize the nature of any associated dose-response relationships.

 

 

  1. Please comment on EPA's determination that the laboratory studies provide a plausible basis for the means to establish a hypothesis concerning the potential for atrazine to cause developmental effects. Also, please comment on whether the overall body of available data is adequate to demonstrate whether or not atrazine causes developmental effects under the conditions described in these studies.

  2. Please comment on EPA's conclusion that given the variability in the available dose-response data across the studies (e.g., an approximately 250-fold difference in reported thresholds for observed developmental effects as well as reports of monotonic and non-monotonic dose-response curves), it is not possible to ascertain the relationship, if any, of atrazine exposure to developmental effects in amphibians.

Lead Discussant: Gerald LeBlanc
Associate Discussant: Werner Kloas, Ph.D. and Robert Denver, Ph.D.

Many of the available studies proposed that aromatase induction results in elevated estrogen levels that lead to feminization (ovotestes/intersex/hermaphroditism) in genetically male amphibians.

  1. Please comment on EPA's conclusion that, to date, aromatase induction by atrazine has not been demonstrated in any anuran in controlled laboratory investigations.

  2. The variability associated with plasma sex steroid concentrations and aromatase activities is high. Is this variability normal? Please comment on any readily apparent or available methodological improvements (e.g., changes in sampling design, analytical techniques) that could efficiently address this variability in future studies.

  3. Please comment on whether there are additional data, other than those summarized in the white paper, that suggest late exposure of amphibians (i.e., juveniles or adults) to estrogens or estrogenic chemicals can induce ovotestes formation.

  4. Please comment on whether there are additional data, other than those summarized in the white paper, that suggest alternative mechanisms that could explain the apparent feminization of genetically-male amphibians.

Lead Discussant: Werner Kloas, Ph.D.
Associate Discussants: Darcy Kelley, Ph.D. and Robert Denver, Ph.D.

With regard to specific endpoints, the Agency does not currently have sufficient information to quantitatively relate gonadal/laryngeal effects to reproductive outcomes. A major underlying uncertainty is the ecological relevance of ovotestes occurrence to the maintenance of anuran populations.

  1. Can the Panel provide sources of data on background rates of ovotestes occurrence in amphibian species and any associated considerations for interpreting this information in the context of the reviewed studies?

  2. Can the Panel characterize any evidence that suggests that the presence of ovotestes in male anurans results in reproductive impairment via reductions in fertility?

  3. The reduction of laryngeal muscle area suggests diminished testosterone in males. If this is found to be a valid observation and if estrogen concentrations do increase as testosterone concentrations decrease, what other endpoints (e.g., secondary sexual characteristics and reproductive behavior) would likely be affected?

Lead Discussant: Sherril Green, Ph.D.
Associate Discussant: Gerald LeBlanc, Ph.D. ,Werner Kloas, Ph.D. and Darcy Kelley, Ph.D.

While some of the available data indicate there may be an association between atrazine exposure and developmental effects in amphibians, the Agency's evaluation of the existing body of laboratory and field studies has determined that there is not sufficient scientific evidence to indicate that atrazine consistently produces effects across the range of amphibian species examined. However, the current body of knowledge has deficiencies and uncertainties that limit its usefulness in assessing potential developmental atrazine effects and the extent of any associated cause-effect and dose-response relationships. Consequently, the Agency has determined that there are not sufficient data to reject the hypothesis that atrazine can cause adverse developmental effects in amphibians. Does the SAP concur with these conclusions? If not, what lines-of-evidence would lead to an alternative conclusion?

Lead Discussant: Peter Delorme, Ph.D.
Associate Discussants: Joel Coats, Ph.D. and Carl Richards, Ph.D.

Assuming the Agency determined an ecological risk assessment with a greater degree of certainty concerning developmental effects of atrazine on amphibians were needed, please comment on EPA's conclusion that additional information is required to evaluate potential causal relationships between atrazine exposure and gonadal development. Please also comment on the added utility, if any, of additional information to interpret the shape of dose-response curves for potential developmental endpoints and the extent to which threshold or non-threshold response relationships can be quantified.

Lead Discussant: Peter Delorme, Ph.D.
Associate Discussants: Joel Coats, Ph.D. and Darcy Kelley, Ph.D.

The Agency has developed a conceptual model from which to develop a set of study protocols for evaluating the potential effects of atrazine on gonadal development in amphibians. The Agency has proposed a research approach using focused, empirical, laboratory studies based on initial investigations with X. laevis followed by selective, confirmatory studies with frog species native to North America.

  1. Please comment on the proposed sequence of study objectives.

  2. Please comment on whether the Agency's first set of proposed studies has accounted for the major sources of uncertainty associated with the potential effects of atrazine on anuran sexual differentiation. In addition to time to metamorphosis, gonadal abnormalities, and sex ratios in the proposed Phase I assays, please comment on any other endpoints that should be considered in this initial phase.

  3. Please also comment on the range, spacing and number of atrazine concentrations that should be employed in the proposed testing sequence to resolve uncertainties in the shape and nature of dose-response relationships for any observed developmental effects.

  4. Please comment on the Agency's recommendation that X. laevis be used as the primary biological model in the proposed studies and whether or not the mechanisms involved in sexual differentiation of the ranid and pipid species are sufficiently similar to predict effects and associated dose-response curves for Rana and/or to efficiently design Rana studies.

  5. In this regard, are there important differences between the species to conclude that any affected developmental processes observed in X. laevis would not occur in Rana?

  6. Alternatively, are there developmental pathways in Rana, but not in X. laevis, that raise concerns about using X. laevis as the primary biological model in any future atrazine studies?

  7. Assuming X. laevis and Rana are sufficiently concordant from a toxicodynamic perspective with regard to potential developmental effects of atrazine, what critical toxicokinetic processes should be considered for extrapolating X. laevis dose-response relationships to Rana and/or for designing subsequent studies with Rana?

Lead Discussant: Carl Richards, Ph.D.
Associate Discussants: Peter Delorme, Ph.D., David Skelly, Ph.D. and Darcy Kelley, Ph.D.

Please be advised that agenda times are approximate. For further information, please contact the Designated Federal Official for this meeting, Mr. Paul Lewis, via telephone: (202) 564-8450; fax: (202) 564-8382; or email:lewis.paul@epa.gov

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
OPEN MEETING

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