Document ID: chunk:federal_register_of_legislation:F2013C00288:reg:1:p6
Version: federal_register_of_legislation:F2013C00288
Segment Type: reg
Provision Reference: reg 1 (pt 6/16)
Character Range: 2065888–2068805

arsenic and its metabolites, the evidence points to weak or non-existent direct mutagenesis (genotoxicity), which is seen only at highly cytotoxic concentrations.
    * Long-term, low-dose exposures to inorganic arsenic (more relevant to human exposure) is likely to cause increased mutagenesis as a secondary effect of genomic instability. While the mechanism of action (MOA) is not fully understood, it is suggested by IARC (2012) that it may be mediated by increased levels of reactive oxygen species, as well as co-mutagenesis with other agents. The major underlying mechanisms observed at low concentrations include the rapid induction of oxidative DNA damage and DNA-repair inhibition, and slower changes in DNA-methylation patterns, aneuploidy, and gene amplification.
    * Inhibition of DNA repair leads to co-carcinogenicity.
 Revision to the WHO guidelines on drinking water (WHO 2011b) adopted a practical value based on the analytical limit of reporting rather than based on a doseresponse approach. The oral slope factor derived by the US has not been used to derive a guideline, as the slope factor is noted by WHO as likely to be an overestimate.

US EPA reviews have retained the use of a non-threshold approach, based on sufficient supporting evidence associated with increased rates of bladder and lung cancer (for inhalation exposures (US EPA 2001)). The US EPA approach adopted follows a review by the NRC (2001) which concluded that '… internal cancers are more appropriate as  end points for risk assessment than non-melanoma skin cancers'. Slope factors relevant for the assessment of these end points range from 0.423 (mg/kg/day)-1. The use of a non-threshold approach (slope factor), however, is more by default by following the US EPA Carcinogenic Guidelines (US EPA 2005), as there remains uncertainty on the carcinogenic MOA for arsenic (Sams et al. 2007). Further research is required to define and review the MOA prior to the US revising the doseresponse approach currently adopted. Inherent in the current US approach (where a non-threshold slope factor is derived) are some key uncertainties that likely result in an overestimate of risk (Boyce et al. 2008), which include (SAB 2005, Brown 2007, Lamm & Kruse 2005 and Chu & Crawford-Brown 2006):
    * the choice of the cancer end point
    * the choice of the mathematical model used to estimate risk (shape of the doseresponse curve at low doses) as there is no clear biological basis for extrapolation
    * the assumptions used to estimate exposure from studies (primarily epidemiological studies).
Review of recent studies presented by Boyce et al. (2008) has indicated that, for carcinogenic effects associated with arsenic exposure, a linear (or non-threshold) doseresponse is not supported (also note discussion by Clewell et al. 2007). This is based on the following:
    * Epidemiological studies (worldwide) that have