Development of a reference dose for the persistent congeners of weathered toxaphene based on in vivo and in vitro effects related to tumor promotion

Abstract

Toxaphene is a mixture of chlorinated camphenes and bornanes that was produced and used in the United States until 1982. 1.3 million tons of toxaphene have been released worldwide. "Technical" toxaphene (TT) consists of a mixture of up to 800 different chemicals, known as congeners. TT weathers in the environment by both biotic and abiotic processes. The human body burden of toxaphene consists of only five persistent congeners that are not metabolized; three of these occur in considerably greater amounts than the other two. Because of the rapid metabolism and excretion of the non-persistent congeners, the persistent congeners that make up the human body burden most likely play a role in eliciting any potential adverse effects. EPA's toxicity assessment for TT is based on the occurrence of liver cancer in rodents, and considerable doubt exists whether this assessment is applicable to weathered toxaphene (WT). Using experimental results from European Union scientists, a reference dose (RfD) was developed for WT based on the three most persistent congeners that comprise the human body burden. The critical effect chosen was tumor promotion and this endpoint is considered protective for other endpoints as well. Although RfDs are typically derived for non-carcinogenic effects, the endpoint of tumor promotion is appropriate for RfD development because the experimental data suggest a dose threshold. The RfD for weathered toxaphene represented by the sum of the three major persistent congeners ( summation 3PC) is 2E-05 mg/kg-day. To apply this reference dose to a particular WT mixture, information is needed regarding the percentage of summation 3PC in the mixture.

Risk Assessment of Toxaphene and its Breakdown Products: Time for a Change?

“…**** NOAEL (for 3PC) as selected by Simon and Manning (2006) based on the mid dose of CLE tested (4.17 mg/kg/week, expressed as uVT) in the Besselink et al (2000) study. The mid dose was designated as the NOAEL by Simon and Manning because of "the difficulty interpreting the in vivo results observed at the highest dose of CLE."…”

“…In the United States, the data by Besselink et al (2000) on the tumor promotion potential of TT and WT were used for a proposed risk assessment model for WT by Simon and Manning (2006). These authors also recommended a reference dose (RfD) (nonlinear) approach to the risk assessment of TT and WT.…”

“…The linearized multistage model is not appropriate for tumor promotion where a nonlinear mode of action is much more likely (Goodman et al, 2000;Simon and Manning, 2006;Leonards et al, 2006). For toxaphene, a linear cancer slope factor approach is not recommended because a nongenotoxic, phenobarbital-like mode of action is the most likely mode of action for TT and in turn for WT.…”

“…Others have proposed the calculation of uncertainty factors based on separate consideration of pharmacokinetic and pharmacodynamic factors due to interspecies variability; with sufficient data on pharmacokinetics or pharmacodynamics, it would be plausible to calculate an uncertainty factor lower than 100 (Ritter et al, 2007). Adjustments for the 3PC should be considered at the same time, by simply comparing the 3PC concentrations in technical toxaphene to the 3PC environmental concentrations, as recommended by Simon and Manning (2006).…”

“…An alternate hypothesis is that the metabolism of these nonpersistent congeners is associated with the carcinogenic process. However, Simon and Manning (2006) proposed that the three persistent congeners (P-26, P-50, and P-62, or 3PC) that make up the majority of the human body burden of toxaphene are the congeners that would most likely be associated with any potential adverse effects. They therefore propose that the 3PC model is a reasonable surrogate for modeling the oncogenicity of WT in humans.…”