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

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 (∑3PC) is 2E−05 mg/kg-day. To apply this reference dose to a particular WT mixture, information is needed regarding the percentage of ∑3PC in the mixture.