Document ID: chunk:federal_register_of_legislation:F2013C00288:reg:1:p7
Version: federal_register_of_legislation:F2013C00288
Segment Type: reg
Provision Reference: reg 1 (pt 7/16)
Character Range: 2068526–2071614

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 repeatedly demonstrated that cancers associated with inorganic arsenic ingestion are observed only in populations exposed to arsenic concentrations in drinking water that are greater than 150 μg/L. In the US, exposures to concentrations in drinking water have only been associated with carcinogenic effects where mean concentrations are greater than 190 µg/L (Schoen et al. 2004).
    * Mechanistic information on how arsenic affects the cellular processes associate with carcinogenicity. This includes consideration that arsenic and its metabolites may modify DNA function through more indirect mechanisms such as inhibition of DNA repair, induction of dysfunctional cell division, perturbation of DNA methylation patterns, modulation of signal transduction pathways (leading to changes in transcriptional controls and the over-stimulation of growth factors), and generation of oxidative stress (ATSDR 2007 and IARC 2012) and that evidence for the indirect mechanisms for genotoxicity identified in in vitro studies have nearly all been at concentrations that are cytotoxic (Klein et al. 2007).
Hence the default approach adopted by the US EPA in adopting a non-threshold approach to the assessment of the carcinogenic effects associated with arsenic exposure is not well supported by the available data. This is consistent with the most recent Australian review available (APVMA 2005). The review conducted considered current information on arsenic carcinogenicity and genotoxicity which noted the following:

'Although exposure to high concentrations of inorganic arsenic results in tumour formation and chromosomal damage (clastogenic effect), the mechanism by which these tumours develop does not appear to involve mutagenesis. Arsenic appears to act on the chromosomes and acts as a tumour promoter rather than as an initiator …'. 'Furthermore, the epidemiological evidence from occupational exposure studies indicates that arsenic acts at a later stage in the development of cancer, as noted with the increased risk of lung cancer mortality with increasing age of initial exposure, independent of time after exposure …' 'Hence arsenic appears to behave like a carcinogen which exhibits a threshold effect. This would also be conceptually consistent with the notion that humans have ingested food and water containing arsenic over millennia and so the presence of a threshold seems likely. Nevertheless the mechanism by which tumour formation develops following arsenic exposure has been and still continues to be a source of intensive scientific investigation.'

On the basis of the above the use of a threshold doseresponse approach for the assessment of carcinogenic effects associated with arsenic exposure is considered appropriate and has been adopted in the derivation of soil HILs.

The review