Comparison of chronic toxicity and carcinogenicity of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) in 2‐year bioassays in female Sprague‐Dawley rats

Abstract

The cancer bioassay for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) conducted by the Dow Chemical company in the mid 70s been used extensively for conducting quantitative cancer risk assessments for human exposure to TCDD. More recently the National Toxicology Program (NTP) conducted a cancer bioassay of similar design as part of its evaluation of the dioxin TEF methodology. This report compares the design and the results of these two cancer bioassays. This comparison confirms, in most cases, previously published and widely used carcinogenic response characteristics with respect to dose, time course, organ selectivity, tumor type and maximum intensity of TCDDinduced carcinogenicity and toxicity in the Sprague-Dawley rat. Specifically increased in the incidences of neoplasms were seen in both studies in the liver, lung and oral mucosa. The most notable difference was the significant increase in the incidence of cholangiocarcinoma of the liver seen in the NTP study but not in the Dow study. The experimental designs for the two studies are similar but some protocol parameters differed such as vehicle, dosing schedule, diet and rat sub-strain utilized. Differences in the shapes of the dose response curves for several neoplasms were noted between the studies, with the NTP study showing non-linearity for all neoplasms. This may result from differences in the experimental protocols as well as divergence in the biological behavior of the different stocks of Sprague-Dawley rat strains used.

Pulmonary Lesions in Female Harlan Sprague-Dawley Rats Following Two-Year Oral Treatment with Dioxin-Like Compounds

“…In these studies, there was an increase in the incidence of neoplasms and non-neoplastic lesions in several organs notably the liver, lung and oral mucosa (National Toxicology Program, 2004a,b,c,d;Walker et al, 2005Walker et al, , 2006Hailey et al, 2005;Jokinen et al, 2003;Nyska et al, 2004Nyska et al, , 2005Tani et al, 2004;Yoshizawa et al, 2005a, b). This present article, one of a series of works highlighting specific findings from NTP dioxin-TEF-evaluation studies, focuses on a comparative analysis of pulmonary effects across these studies.…”

Assessment of the cancer potential of methanol

“…In that one study, two males (2.67%) had ear duct carcinomas and six (8%) of the females did. In the NTP Sprague-Dawley rat database (Walker et al, 2006), none of the 371 females had ear duct carcinomas. Along with the PWG evaluation of ear duct carcinomas from the RF aspartame study, the historical database for ear duct carcinomas indicates that the ear duct carcinomas in the methanol study should be questioned.…”

“…Lympho-immunoblastic lymphoma was not reported in any study. The National Toxicology Program conducted a series of seven carcinogenicity studies in female Sprague-Dawley rats (Walker et al, 2006). The control data from those studies included 371 females and 0 males (Table 19).…”

Synergism between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumor incidence in mice

“…Epidemiological studies show that exposure to TCDD increases all cancer mortality, including lung cancer [1,2]. Longterm treatment (2 years) of TCDD leads to the development of tumors of the liver, thyroid, lung, and other sites in female rats [3]. In experimental studies, TCDD activates aryl hydrocarbon receptors (AhRs), which change many gene expressions and possibly affect cancer development [4].…”