5/27/04

Notes on call w/Cooper & Darney, ORD; Sheppard and Birgfeld, OAP

Overview—

OAP:  We are now looking at female reproductive issues.  We are looking
at Yamada vs. WIL.  The purpose is to see if we should develop a new AEL
for risk assessment.

	We will need:	UF for rats to humans

			UF for interhuman variability

Before—In June proposal, looking at male reproductive effects.  We
calculated a BMDL of ~ 169 ppm.

For female reproductive effects, we were not able to benchmark—models
didn’t fit well—

Issue:  ordinal scale (regularity) vs. continuous (cycle length) 

How to do, when some of the animals were acyclic?

ORD:  Which parts of the ovarian cycle are you examining?

What are the lengths in estrous vs. diestrous portions of cycle?

			Diestrous(follicles not growing; prolonged

4 to 5 days is typical for the estrous cycle for ovary

Cycle may stop or be extended because:

An ovarian effect—withered away

or  

“pseudo-pregnant”  -high levels of progesterone

The target site may be the central nervous system or the pituitary

In Yamada, there were no growing antral follicles, as would be expected
in a pseudo-pregnant animal.

Based on Yamada, we would expect reduced litter size, prolonged
diestrous—found in WIL.

Midcycle surges of LH and FSH (pituitary hormones) precede
ovulation—measuring LH and FSH in diestrous may not mean much.

OAP:  Should impacts on the number of antral follicles be considered a
LOAEL?

What is the relevance, esp. to humans: 

ORD:  If no cycle at all—can’t get pregnant

But—there are also male effects

Not clear if male or female only

In women—population of women with different ages, different cycle
types

High sensitivity—might interact with blood pressure medication

WIL( 250 ppm LOAEL for estrous cycle length   100 ppm NOEC for both
genders

OAP: Could we do a benchmark for females?  If so, what health effect?

On estrous cycle length?  

ORD:  Yes, or even better would be the number of cycles in 3 weeks of
data collection 

Will avoid the problem of how to address cycle length in acyclic animals


Dependency on progesterone does matter for humans, too

if mode of action is through the pituitary – may have effects in both
men and women—an endocrine disruptor

if direct ovarian effect, definitely an impact

Yamada—thinks 1- and 2-BP have different modes of action

OAP:  Is it possible to do a BMD?  We will follow up w/Yamada to get raw
data.

