Experience with new testing guidelines with endocrine-sensitive
end-points
R. W. Tyl
Center for Life Sciences and Toxicology, RTI International,
3040 Cornwallis Road, P.O.Box 12194, Research Triangle Park, NC 27709-2194,
USA
Abstract: Concerns about the effects of endocrine disruptors
on humans and wildlife have resulted in revised governmental testing
guidelines (e.g., U.S. Environmental Protection Agency, Organization
for Economic Cooperation and Development, U.S. Food and Drug Administration),
adding endpoints to enhance their capability to detect endocrine active
compounds. Based on experience with these testing guidelines, I present
my opinions and data on study design, performance, results, endpoints,
interpretation, and recommendations for improvement. New regulatory
endpoints must be reproducible, robust, sensitive, relevant, and consistent.
These new endpoints are appropriate: anogenital distance, examination
of culled pups on postnatal day 4, examination for retained nipples/areolae
in preweanling males, weanling necropsy, acquisition of puberty in offspring,
prebreed estrous cyclicity, reproductive organ weights and histopathology,
and andrology. Endpoints considered not appropriate are ovarian primordial
follicle counts, stage of estrous for parental females at demise, and
single blood sample at necropsy to measure circulating levels of relevant
hormones. In conclusion: (1) regulatory guidelines represent only the
minimum requirements and should/will change as science improves and
scientific and societal concerns arise; (2) scientists must interact
to identify and refine new methods, endpoints, and mechanisms; (3) the
objective of these studies is to provide good science and useful information
for risk assessment. Regulatory agencies should convene workshops with
stakeholders to discuss issues such as new fundamental/applied information,
mechanisms, and current and new endpoints. Interactions will lead to
enhanced science, periodic revisions of testing guidelines, and improved
risk assessment.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
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