US National Toxicology Program's scientific peer review of low-dose effects of endocrine disrupting compounds. October 2000.

This paper demonstrates that DDT and HCH both induce estrogenic changes in mice when exposed chronically to very low doses of these compounds. Most alarming according to the authors, is the fact that they observed statistically significant results within the range of background exposures experienced by people in the real world. More...

Gupta shows that bisphenol A, arochlor 1016 (a PCB mixture) and DES enlarge the adult prostates of mice exposed in utero to very low levels, confirming effects first found by Fred vom Saal. More...

Gray, LE, J Ostby, E Monosson and WR Kelce. 1999. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicology and Industrial Health 15: 48-64.

Previous studies of the impact of vinclozilin, a widely-used fungicide, had reported that the lowest level of contamination at which an impact could be produced in developing offspring was 50 to 100+ milligrams/kilogram (parts per million, delivered per day to a pregnant female). Gray et al. report here that when they examine developmental endpoints known to be sensitive to anti-androgenic drugs, they find vinclozilin produces detectable effects at the lowest levels used in their experiment, 3.125 parts per million. The impacts detected included hypospadias (down to 50 ppm), ectopic testes (100 ppm), the number of nipples (3.125 ppm) and sperm count declines. Male pups exposed to 100 ppm vinclozolin were about 70% female-like in their phenotype. More...

Howdeshell, K, AK Hotchkiss, KA Thayer, JG Vandenbergh and FS vom Saal. 1999. Plastic bisphenol A speeds growth and puberty. Nature 401: 762-764.

Howdeshell et al. found that female mice, exposed in the womb by delivering low doses of bisphenol A (2.4 parts per billion) to the mother in food, pass a milestone in sexual development significantly earlier than unexposed mice. They also show that position in the womb interacts with contamination: those females positioned between female litter mates were most effected by bisphenol a, while those between males were least effected. More...

Christian and Gillies demonstrate impacts of octylphenol at parts per trillion levels in a cell culture preparation using hypothalamic cells taken and cultured from fetal rat brains. More...

Welshons, WV, SC Nagel, KA Thayer, BM Judy, and FS vom Saal. 1999. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prosate size in mice. Toxicology and Industrial Health 15:12-25.

Experimental manipulation of serum concentrations of several synthetic estrogenic compounds causes an increase in the prostate size of the exposed male mice once they reach adulthood. The concentration of the contaminants necessary to produce this change is extremely low: as little as 2 parts per billion of bisphenol A, .02 parts per billion DES, and 20 parts per billion methoxychlor caused significant increases. The research on DES and bisphenol A had been published earlier. This paper presents new data on methoxychlor.

Porter, WP, JW Jaeger and IH Carlson. 1999. Endocrine, immune and behavioral effects of aldicarb (carbamate), atrazine (triazine) and nitrate (fertilizer) mixtures at groundwater concentrations. Toxicology and Industrial Health 15: 133-150.

Porter et al. experiment with combinations of two common pesticides and a fertilizer, exposing adult male mice to mixtures and concentrations within the range of exposures regularly encountered in human drinking water in agricultural regions in mid-West of the United States. Exposure was through voluntary consumption of drinking water. Measuring endocrine, immune and behavioral variables, they observed significant changes in endocrine, immune and behavior in response to mixtures of the contaminants, but rarely in response to single compounds at the same concentration. More...

Porter et al. also comment on the inadequacies of current testing protocols used to establish regulatory standards. More...

Rice, DC and S Hayward 1999. Effects of postnatal exposure of monkeys to a PCB mixture on concurrent random interval-random interaval and progressive ratio performance. Neurotoxicology and Teratology 21:47-58.

Rice and Hayward report that male monkeys that had been dosed with a low level PCB mixture (7.5 parts per billion, representative of the doses typically found in human breast milk) differed significantly from controls in one of the measures used to assess their behavior. "The PCB-treated monkeys emitted more responses than controls over the first few sessions of the PR (progressive ratio schedule), which may be indicative of retarded acquisition of their steady state PR performance."

Rice has commented in scientific lectures that the treatment level (7.5 ppb) was misreported to her before the onset of the experiments, and that had it been reported properly (the value given was much higher than 7.5 ppb) she would not have done the experiments because it seemed unlikely there would be any impact.

As discussed in Our Stolen Future (Chapter 7), RE Peterson's lab has shown that extremely low doses of dioxin experienced in utero can disturb reproductive function and behavior in adulthood (Mably et al. 1992a,b,c). Here, MacLusky et al. show that fetal exposure to a low level of dioxin (0.7 µg/kg or 0.7 ppb) "disturbed sexual differentiation of reproductive behavior, potentiating the expression of feminine sexual behavior and reducing masculine behavior."

They also studied cognitive function in rats exposed in utero. Here their experiments revealed an enhancement in rat performance in maze tests, comparing treated animals to controls. Treated animals committed significantly fewer errors.

More...

Rice, DC. 1998. Effects of postnatal exposure of monkeys to a PCB mixture on spatial discrimination reversal and DRL performance. Neurotoxicology and Teratology 20(4):391-400.

This is one paper in a series by Deborah Rice and by Rice and Stephen Hayward that explore the consequences of low level neonatal PCB exposure in monkeys for their subsequent performance in a variety of behavioral tests.

The experiments involved monkeys that had been exposed at birth to different levels of PCBs. The exposures were within the range of levels measured in Canadian women (Rice did this work on the scientific staff of Health Canada, in Ottowa, Ontario, Canada). Specifically, blood PCB levels were 0.30-0.37 ppb for controls and 1.84-2.84 ppb for treated levels). This exposure was achieved by dosing the infant chimps with7.5 ppb/day of a PCB mixture representative of that found in human milk.

Rice has commented in scientific lectures that the treatment level (7.5 ppb) was misreported to her before the onset of the experiments, and that had it been reported properly (the value given was much higher than 7.5 ppb) she would not have done the experiments because it seemed unlikely there would be any impact.

Nagel et al. present data demonstrating that bisphenol A can alter fetal mouse development at extraordinarily low levels of exposure. Pregnant female mice were fed bisphenol A mixed in corn oil at two concentrations: 2 and 20 micrograms per kg of body weight (parts per billion). Prostate weight was then determined at the age of 6 months. Males exposed to both levels of bisphenol A experienced an increase in prostate size.

These results are profoundly important for two reasons.

• They demonstrate the remarkable sensitivity of fetal development to low level hormone disruption.
• They reveal bisphenol A effects on mice at levels, when corrected for body size differences, are within the range of bisphenol A regularly ingested by people as a result of the use of polycarbonate plastics in common products.

vom Saal, F, BG Timms, MM Montano, P Palanza, KA Thayer, SC Nagel, MD Dhar, VK Ganjam, S Parmigiani and WV Welshons. 1997. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proceedings of the National Academy of Sciences USA 94:2056-61.

• Relative to controls, males treated with as little as 0.02 nanograms/gram (0.02 parts per billion) DES had heavier prostate glands.
• Relative to controls, males that experienced a change in free serum estradiol less of than one part per trillion had heavier prostate glands (by 27%), a 6-fold increase in the number of androgen receptors in the prostate, a 2-fold increase in the number of androgen receptors per prostate cell, and a 40% increase in the number of cells per prostate.
• For both DES and estradiol, the dose response curve relating exposure to impact were non-monotonic, i.e., intermediate exposures produced larger prostates than low or high exposures. While dose-reponse relationships like this are common in physiological processes, they are not expected by traditional toxicology. More...

Gaylor, DW. 1992. Incidence of developmental defects at the No Observed Adverse Effect Level (NOAEL). Regulatory Toxicology and Pharmacology 15:151-160.

"The NOAEL is the dose at which it is judged there is no significant increase in the incidence of any important adverse biological effect." The NOAEL level is used to establish the reference dose, or RfD. Setting the RfD usually involves looking at animal data, determining a NOEAL, and then using a safety factor (for example, 10) to allow for greater sensitivity of some people compared to others. It is assumed that exposures at or below the RfD generally result in negligible effects.

Gaylor asked about the incidence of adverse developmental for expsoures at the NOAEL level. He found that in 24% of cases, the observed risk of abnormal fetuses exceeded 1% at the NOAEL.

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