Adverse effects in risk assessment: modeling polychlorinated biphenyls and thyroid hormone disruption outcomes in animals and humans.

There is a growing need for quantitative approaches to extrapolate relationships between chemical exposures and early biological perturbations from animals to humans given increasing use of biological assays to evaluate toxicity pathways. We have developed such an approach using polychlorinated biphenyls (PCBs) and thyroid hormone (TH) disruption as a case study. We reviewed and identified experimental animal literature from which we developed a low-dose, linear model of PCB body burdens and decrements in free thyroxine (FT(4)) and total thyroxine (TT(4)), accounting for 33 PCB congeners; extrapolated the dose-response from animals to humans; and compared the animal dose-response to the dose-response of PCB body burdens and TH changes from eleven human epidemiological studies. We estimated a range of potencies for PCB congeners (over 4 orders of magnitude), with the strongest for PCB 126. Our approach to developing toxic equivalency models produced relative potencies similar to the toxicity equivalency factors (TEFs) from the World Health Organization (WHO). We generally found that the dose-response extrapolated from the animal studies tends to under-predict the dose-response estimated from human epidemiological studies. A quantitative approach to evaluating the relationship between chemical exposures and TH perturbations, based on animal data can be used to assess human health consequences of thyroid toxicity and inform decision-making.

[1]  J. Sunyer,et al.  Organochlorine compounds, iodine intake, and thyroid hormone levels during pregnancy. , 2009, Environmental science & technology.

[2]  M. Verity.  Ca(2+)-dependent processes as mediators of neurotoxicity. , 1992, Neurotoxicology.

[3]  Kevin M Crofton,et al.  Thyroid disrupting chemicals: mechanisms and mixtures. , 2008, International journal of andrology.

[4]  H. Anderson,et al.  Relationships of Thyroid Hormones with Polychlorinated Biphenyls, Dioxins, Furans, and DDE in Adults , 2007, Environmental health perspectives.

[5]  S. Yamada,et al.  A Novel Mechanism for Polychlorinated Biphenyl-Induced Decrease in Serum Thyroxine Level in Rats , 2007, Drug Metabolism and Disposition.

[6]  J. Sunyer,et al.  Association between serum concentrations of hexachlorobenzene and polychlorobiphenyls with thyroid hormone and liver enzymes in a sample of the general population , 2001, Occupational and environmental medicine.

[7]  J. Bailar,et al.  Toxicity Testing in the 21st Century: A Vision and a Strategy , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[8]  M. Lopez-Espinosa,et al.  Association between thyroid hormone levels and 4,4'-DDE concentrations in pregnant women (Valencia, Spain). , 2009, Environmental research.

[9]  K. Crofton,et al.  Developmental exposure to polychlorinated biphenyls (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats. , 1995, Toxicology and applied pharmacology.

[10]  Fred Parham,et al.  Upstream adverse effects in risk assessment: a model of polychlorinated biphenyls, thyroid hormone disruption and neurological outcomes in humans. , 2012, Environmental research.

[11]  K. Sundet,et al.  Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults. , 2003, Pediatrics.

[12]  C DeRosa,et al.  Using structural information to create physiologically based pharmacokinetic models for all polychlorinated biphenyls. , 1997, Toxicology and applied pharmacology.

[13]  P. Ayotte,et al.  Thyroid Function and Plasma Concentrations of Polyhalogenated Compounds in Inuit Adults , 2009, Environmental health perspectives.

[14]  J. Jacobson,et al.  Thyroid Hormone Levels of Pregnant Inuit Women and Their Infants Exposed to Environmental Contaminants , 2009, Environmental health perspectives.

[15]  J. Meeker,et al.  Serum PCBs, p,p'-DDE and HCB predict thyroid hormone levels in men. , 2007, Environmental research.

[16]  C. Klaassen,et al.  Differential effects of polychlorinated biphenyl congeners on serum thyroid hormone levels in rats. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  Jerry L. Campbell,et al.  Effect of PCB 126 on hepatic metabolism of thyroxine and perturbations in the hypothalamic-pituitary-thyroid axis in the rat. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[18]  F. Collins,et al.  Transforming Environmental Health Protection , 2008, Science.

[19]  H. Tilson,et al.  Neurochemical effects of polychlorinated biphenyls: an overview and identification of research needs. , 1997, Neurotoxicology.

[20]  R. Zoeller.  Polychlorinated Biphenyls as Disruptors of Thyroid Hormone Action , 2001 .

[21]  A. Salmon,et al.  Development of TEFs for PCB congeners by using an alternative biomarker--thyroid hormone levels. , 2010, Regulatory toxicology and pharmacology : RTP.

[22]  R. Peterson,et al.  Effects of gestational and lactational exposure to coplanar polychlorinated biphenyl (PCB) congeners or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thyroid hormone concentrations in weanling rats. , 1995, Toxicology letters.

[23]  Y. Jacquemyn,et al.  Distribution of PCBs and organochlorine pesticides in umbilical cord and maternal serum. , 2002, The Science of the total environment.

[24]  C. Tohyama,et al.  The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  Mitchell D. Erickson,et al.  Analytical Chemistry of PCBs , 1986 .

[26]  M. Greenberg,et al.  Toxicity Testing in the 21st Century , 2009, Risk analysis : an official publication of the Society for Risk Analysis.

[27]  S. Schantz,et al.  Effects of perinatal exposure to specific PCB congeners on thyroid hormone concentrations and thyroid histology in the rat. , 1993, Toxicology letters.

[28]  M. Kempers,et al.  Quality of life, developmental milestones, and self-esteem of young adults with congenital hypothyroidism diagnosed by neonatal screening. , 2008, The Journal of clinical endocrinology and metabolism.

[29]  Kevin M. Crofton,et al.  Mode of Action: Developmental Thyroid Hormone Insufficiency—Neurological Abnormalities Resulting From Exposure to Propylthiouracil , 2005, Critical reviews in toxicology.

[30]  V. Nelen,et al.  Association of Thyroid Hormone Concentrations with Levels of Organochlorine Compounds in Cord Blood of Neonates , 2007, Environmental health perspectives.

[31]  C. Klaassen,et al.  Effects of Microsomal Enzyme Inducers on Thyroid Follicular Cell Proliferation and Thyroid Hormone Metabolism , 2001, Toxicologic pathology.

[32]  Kevin M. Crofton,et al.  Thyroid-Disrupting Chemicals: Interpreting Upstream Biomarkers of Adverse Outcomes , 2009, Environmental health perspectives.

[33]  D. Mergler,et al.  Gender differences in the effects of organochlorines, mercury, and lead on thyroid hormone levels in lakeside communities of Quebec (Canada). , 2008, Environmental research.

[34]  K. Banovac,et al.  Alterations in thyroxine metabolism produced by cutaneous application of microscope immersion oil: effects due to polychlorinated biphenyls. , 1976, Endocrinology.

[35]  N. Holland,et al.  Effects of exposure to polychlorinated biphenyls and organochlorine pesticides on thyroid function during pregnancy. , 2008, American journal of epidemiology.

[36]  S. Lafranchi,et al.  Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. , 2005, The Journal of pediatrics.

[37]  T. Visser,et al.  Interactions of Persistent Environmental Organohalogens With the Thyroid Hormone System: Mechanisms and Possible Consequences for Animal and Human Health , 1998, Toxicology and industrial health.

[38]  K. Crofton,et al.  Screening methods for thyroid hormone disruptors. , 1999, Environmental health perspectives.

[39]  H. Tilson,et al.  Polychlorinated biphenyls and the developing nervous system: cross-species comparisons. , 1990, Neurotoxicology and teratology.

[40]  C. Klaassen,et al.  UDP-glucuronosyltransferase inducers reduce thyroid hormone levels in rats by an extrathyroidal mechanism. , 1992, Toxicology and applied pharmacology.

[41]  Amy D. Kyle,et al.  Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making , 2008, Environmental health perspectives.

[42]  Philippe Grandjean,et al.  Comparison of polychlorinated biphenyl levels across studies of human neurodevelopment. , 2003, Environmental health perspectives.

[43]  W. H. Carter,et al.  Thyroid-Hormone–Disrupting Chemicals: Evidence for Dose-Dependent Additivity or Synergism , 2005, Environmental health perspectives.

[44]  R. Zoeller,et al.  Environmental chemicals impacting the thyroid: targets and consequences. , 2007, Thyroid : official journal of the American Thyroid Association.

[45]  B. Seo,et al.  Developmental Exposure to Polychlorinated Biphenyls or Dioxin: Do Changes in Thyroid Function Mediate Effects on Spatial Learning? , 1997 .

[46]  J. Vena,et al.  Exploring associations between serum levels of select organochlorines and thyroxine in a sample of New York state sportsmen: the New York State Angler Cohort Study. , 2003, Environmental research.