The U.S. EPA Science Advisory Board Evaluation (2001) of the EPA Dioxin Reassessment

doi:10.1006/rtph.2002.1580

Regulatory Toxicology and Pharmacology

Volume 36, Issue 2, October 2002, Pages 211-219

https://doi.org/10.1006/rtph.2002.1580 Get rights and content

Abstract

The U.S. Environmental Protection Agency (EPA) began a “reassessment” of the risks posed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) and related chemicals in 1991 and issued an interim report in 1994. In 1995, the Science Advisory Board (SAB) reviewed this document and requested revisions. After considerable additional work, EPA issued its final draft report in September 2000. A new EPA SAB reviewed this draft and issued its recommendations in June 2001. This group of scientists offered suggestions to EPA on the following topics, which are discussed in some detail in this article: classification as a “known” human carcinogen, how to estimate the carcinogenic potency, the possible significance of the noncancer hazard, the proper dose metric for cancer and noncancer effects, the uncertainties inherent in the toxicity equivalency factor approach, use of the margin of exposure approach, adequacy of the exposure assessment, body burden calculations, risks to breast feeding children, nonmonotonic responses (U- or J-shaped dose–response curves, or hormetic effect), the possible significance of naturally occurring dioxin-like chemicals, and risks to special populations. The basis for the recommendations, as generally presented in the SAB report, is described here. A discussion of some of the recently published work within the regulatory and scientific communities that has been issued since the SAB report is also presented.

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant known to exhibit toxic effects on the male reproductive system, including the epididymus and spermatozoa. However, the mechanism(s) that mediate dioxin toxicity in spermatozoa remain unclear. The aim of the present study was to investigate whether exposure to TCDD would cause a loss in mitochondrial membrane potential (Δψ_m) in spermatozoa and whether such an effect is mediated by the Ah receptor (AhR). Exposure of C57BL/6 male mice to TCDD at concentrations of 0.1–50 μg/kg for 24 h caused a dose-dependent loss of Δψ_m in epididymal spermatozoa compared to spermatozoa from vehicle-treated mice. However, this effect was not apparent in spermatozoa from AhR knockout (KO) mice. Exposure of spermatozoa from C57BL/6 mice to 1 nM or 5 nM TCDD in vitro also induced loss of Δψ_m. TCDD-exposed C57BL/6 mice failed to exhibit changes in the morphology of testes and epididymus, and did not show any increase in number of apoptotic germ cells. In addition, comparison of reactive oxygen species (ROS) production in spermatozoa from vehicle- and TCDD-treated mice indicated that exposure to TCDD resulted in elevated ROS levels in the spermatozoa from TCDD-treated mice. Moreover, blockade of ROS production by pretreatment with ROS scavenger N-acetylcysteine (NAC) mitigated the loss of Δψ_m following TCDD exposure. Taken together, these data suggest that direct exposure of spermatozoa to TCDD triggers loss of Δψ_m that is mediated by AhR-dependent production of ROS.
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Citation Excerpt :
The tolerable daily intake (TDI), a reference value for ensuring that acceptable levels of exposure are not exceeded, determined by the World Health Organization for dioxin TEQ in 1998 is 1–4 pg/kg bodyweight (WHO, 1999). The USEPA has not released a reference dose (RfD) despite suggestions from the Science Advisory Board that they do so (Paustenbach, 2002). The levels of PCDDs, PCDFs, and PCBs in foodstuffs have dropped several fold (on a TEQ basis) since the 1970s (Hays and Aylward, 2003), but these chemicals are highly persistent and exposure continues.
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^☆: This paper was presented at the 21st International Symposium on Halogenated Environmental Organic Pollutants and POPs (e.g., Dioxin 2001 meeting) in Kyongju, Korea (September 2001).

²: To whom correspondence should be addressed. Fax: (650) 688-1799. E-mail: [email protected].

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Regular ArticleThe U.S. EPA Science Advisory Board Evaluation (2001) of the EPA Dioxin Reassessment☆

Abstract

Regul. Toxicol. Pharmacol

Ecotoxicol. Environ. Saf

Toxicol. Appl. Pharmacol

Dioxin and cancer

Regul. Toxicol. Pharmacol

Temporal Trends in Human TCDD Body Burden: Decreases Over Three Decades and Implications for Exposure Levels

J. Exposure Anal. Environ. Epidemiol

Relative susceptibility of animals and humans to the cancer hazard posed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using internal measures of dose

Environ. Sci. Technol

Defining hormesis

Hum. Exp. Toxicol

The frequency of U-shaped dose responses in the toxicological literature

Toxicol. Sci

Scientific foundations of hormesis

Crit. Rev. Toxicol

Fed. Regist

Regular Article
The U.S. EPA Science Advisory Board Evaluation (2001) of the EPA Dioxin Reassessment☆