A Mechanism for the induction of renal tumours in male Fischer 344 rats by short-chain chlorinated paraffins

Abstract

Short-chain chlorinated paraffins (SCCPs) cause kidney tumours in male rats, but not in female rats or mice of either sex. Male rat-specific tumours also occur in rats dosed with a range of compounds including 1,4- dichlorobenzene (DCB) and d-limonene (DL). These compounds bind to a male rat-specific hepatic protein, alpha-2-urinary globulin (α2u), and form degradationresistant complexes in the kidney. The resulting accumulation of α2u causes cell death and sustained regenerative cell proliferation, which in turn leads to the formation of renal tumours. To investigate whether the SCCP, Chlorowax 500C (C500C), causes tumours via the accumulation of α2u male rats were orally dosed with either C500C (625 mg/kg of body weight), DCB (300 mg/kg of body weight), or DL (150 mg/kg of body weight) for 28 consecutive days. An increase in renal α2u and cell proliferation was observed in DCB- and DL-treated rats but not in C500C-treated rats. C500C caused peroxisome proliferation and a down-regulation of α2u synthesis in male rat liver. This down-regulation occurred at the transcriptional level. Since less α2u was produced in C500C-treated rats, there was less available for accumulation in the kidney hence a typical α2u nephropathy did not appear. However, the administration of a radiolabelled SCCP, [14C]polychlorotridecane (PCTD), to male rats demonstrated its binding to renal α2u. Thus, it is possible that SCCPs bind to α2u and cause a slow accumulation of the protein in the kidney followed by delayed onset of α2u nephropathy. As a consequence of these findings in the current experiments, while evidence exists implicating α2u-globulin in the molecular mechanism of action of the C500C, the classic profile of a α2u-globulin nephropathy seen with other chemicals such as DCB and DL was not reproduced during this experimental protocol.

Scientific Opinion on Mineral Oil Hydrocarbons in Food

“…The accumulated protein is cytotoxic and cell destruction stimulates surviving cells to proliferate. As described below for compounds such as NAP, this would increase the probability of selection or occurrence of initiated cells and hence of cancer (Warnasuriya et al, 2010). This mode of action is not relevant to humans, as there is no protein equivalent to α 2u -globulin present at urinary concentrations anywhere near comparable with those of α 2u -globulin in male rats (IARC, 1993).…”

Short- and medium-chain chlorinated paraffins in sediments from the middle reaches of the Yangtze River: Spatial distributions, source apportionment and risk assessment

“…They can enter into the environment during the production, transportation, use and disposal of CPs and CP-containing materials. Considering the potential for long-range transport (Tomy et al, 1999), persistence (Iozza et al, 2008), bioaccumulation (Fisk et al, 2000) and toxicity (Warnasuriya et al, 2010), SCCPs have been listed as candidate persistent organic pollutants (POPs) in the Stockholm Convention. The use of SCCPs in metal-and leather-working has been restricted in the European Union since 2004 because of their high toxicities (European Commission, 2002).…”

Short-chain chlorinated paraffins in marine organisms from the Pearl River Estuary in South China: Residue levels and interspecies differences

“…In general, CPs are divided into three groups according to their carbon chain length: short chain CPs (C 10-13 , SCCPs), medium chain CPs (C 14-17 , MCCPs) and long chain CPs (C 18-30 , LCCPs) (Feo et al, 2009). Among different CP groups, SCCPs have attracted increasing attention in the last decade due to their persistence (Iozza et al, 2008), bioaccumulation (Houde et al, 2008;Zeng et al, 2011a;Basconcillo et al, 2015), toxicity to organisms (Warnasuriya et al, 2010;Geng et al, 2015Geng et al, , 2016, and high potential for long-distance atmospheric transport (Reth et al, 2006;Strid et al, 2013). SCCPs have been placed on the toxic release inventory in the European Union, Japan, Canada, and the United States, and are classified as priority toxic substances in the United States (UNEP, 2015a).…”