PFOA is a peroxisome proliferator (PPAR agonist) and exerts morphological and biochemical effects characteristic of PPAR agonists. These effects include increased beta-oxidation of fatty acids, increases in several cytochrome P-450 (CYP450)-mediated reactions, and inhibition of the secretion of very low-density lipoproteins and cholesterol from the liver. These effects on lipid metabolism and transport result in a reduction of cholesterol and triglycerides in serum and an accumulation of lipids in the liver. The triad of tumors observed (liver, Leydig cell, and pancreatic acinar-cell) is typical of many PPAR agonists and is believed to involve nongenotoxic mechanisms. The hepatocellular tumors observed in rats are likely to have been the result of the activation of the peroxisome proliferator activated receptor alpha (PPARalpha). The tumors observed in the testis (Leydig-cell) have been hypothesized to be associated with an increased level of serum estradiol in concert with testicular growth factors. The mechanism responsible for the acinar-cell tumors of the pancreas in rats remains the subject of active investigation. The mechanism resulting in the hepatocellular tumors in rats (PPARalpha activation) is not likely to be relevant to humans. Similarly, the proposed mechanism for Leydig-cell tumor formation is of questionable relevance to humans. Acinar tumors of the pancreas are rare in humans, and the relevance of the these tumors, as found in rats, to humans is uncertain. Epidemiological investigations and medical surveillance of occupationally exposed workers have not found consistent associations between PFOA exposure and adverse health effects.

The toxicology of perfluorooctanoate.

Background: Exposure to disinfection byproducts in drinking water has been associated with an increased risk of bladder cancer. We pooled the primary data from 6 case-control studies of bladder cancer that used trihalomethanes as a marker of disinfection byproducts. Methods: Two studies were included from the United States and one each from Canada, France, Italy, and Finland. Inclusion criteria were availability of detailed data on trihalomethane exposure and individual water consumption. The analysis included 2806 cases and 5254 controls, all of whom had measures of known exposure for at least 70% of the exposure window of 40 years before the interview. Cumulative exposure to trihalomethanes was estimated by combining individual year-by-year average trihalomethane level and daily tap water consumption. Results: There was an adjusted odds ratio (OR) of 1.24 in men exposed to an average of more than 1 g/L (ppb) trihalomethanes compared with those who had lower or no exposure (95% confidence interval [CI] 1.09 ‐1.41). Estimated relative risks increased with increasing exposure, with an OR of 1.44 (1.20 ‐1.73) for exposure higher than 50 g/L (ppb). Similar results were found with other indices of trihalomethane exposure. Among women, trihalomethane exposure was not associated with bladder cancer risk (0.95; 0.76 ‐1.20). Conclusions: These findings strengthen the hypothesis that the risk of bladder cancer is increased with long-term exposure to disinfection byproducts at levels currently observed in many industrialized countries. (Epidemiology 2004;15: 357‐367)

Disinfection byproducts and bladder cancer: a pooled analysis.

Effects of perfluorooctanoic acid exposure during pregnancy in the mouse.

http://ruby.fgcu.edu/Courses/ndemers/Current%20topics%20endocrine/15%20yrs%20afterWingspread%20EDCs2008.pdf

Fifteen Years after Wingspread -Environmental Endocrine Disrupters and Human and Wildlife Health : Where We are Today and Where We Need to Go

Changes in puberty timing have implications for the treatment of individual children, for the risk of later adult disease, and for chemical testing and risk assessment for the population. Children with early puberty are at a risk for accelerated skeletal maturation and short adult height, early sexual debut, potential sexual abuse, and psychosocial difficulties. Altered puberty timing is also of concern for the development of reproductive tract cancers later in life. For example, an early age of menarche is a risk factor for breast cancer. A low age at male puberty is associated with an increased risk for testicular cancer according to several, but not all, epidemiologic studies. Girls and, possibly, boys who exhibit premature adrenarche are at a higher risk for developing features of metabolic syndrome, including obesity, type 2 diabetes, and cardiovascular disease later in adulthood. Altered timing of puberty also has implications for behavioral disorders. For example, an early maturation is associated with a greater incidence of conduct and behavior disorders during adolescence. Finally, altered puberty timing is considered an adverse effect in reproductive toxicity risk assessment for chemicals. Recent US legislation has mandated improved chemical testing approaches for protecting children's health and screening for endocrine-disrupting agents, which has led to changes in the US Environmental Protection Agency's risk assessment and toxicity testing guidelines to include puberty-related assessments and to the validation of pubertal male and female rat assays for endocrine screening.

https://pediatrics.aappublications.org/content/pediatrics/121/Supplement_3/S218.full.pdf

Public Health Implications of Altered Puberty Timing

In 1996, the US Environmental Protection Agency was given a mandate by Congress to develop a screening program that would evaluate whether variously identified compounds could affect human health by mimicking or interfering with normal endocrine regulatory functions. Toward this end, the Agency chartered the Endocrine Disruptor Screening and Testing Advisory Committee in October of that year that would serve to recommend a series of in vitro and in vivo protocols designed to provide a comprehensive assessment of a chemical's potential endocrine-disrupting activity. A number of these protocols have undergone subsequent modification by EPA, and this review focuses specifically on the revised in vivo screening procedure recommended under the title Research Protocol for Assessment of Pubertal Development and Thyroid Function in Juvenile Female Rats. Background literature has been provided that summarizes what is currently known about pubertal development in the female rat and the influence of various forms of pharmaceutical and toxicological insult on this process and on thyroid activity. Finally, a section is included that discusses technical issues that should be considered if the specified pubertal endpoints are to be measured and successfully evaluated.

Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual maturation and thyroid activity in the female rat. A focus on the EDSTAC recommendations

Sharon K. Balchak

Papers

Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual maturation and thyroid activity in the female rat. A focus on the EDSTAC recommendations

Influence of the drinking water disinfection by-product dibromoacetic acid on rat estrous cyclicity and ovarian follicular steroid release in vitro