Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach

Abstract

The biologic effects of inorganic arsenic predominantly involve reaction of the trivalent forms with sulfhydryl groups in critical proteins in target cells, potentially leading to various toxicologic events including cancer. This mode of action is a threshold process, requiring sufficient concentrations of trivalent arsenic to disrupt normal cellular function. Nevertheless, cancer risk assessments for inorganic arsenic have traditionally utilized various dose-response models that extrapolate risks from high doses assuming low-dose linearity without a threshold. We present here an approach for a cancer risk assessment for inorganic arsenic in drinking water that involves considerations of this threshold process. Extensive investigations in mode of action analysis, in vitro studies (>0.1 mM), and in animal studies (>2 mg/L in drinking water or 2 mg/kg of diet), collectively indicate a threshold basis for inorganic arsenic-related cancers. These studies support a threshold for the effects of arsenic in humans of 50-100 mg/L in drinking water (about 65 mg/L). We then evaluate the epidemiology of cancers of the urinary bladder, lung, and skin and non-cancer skin changes for consistency with this calculated value, focusing on studies involving low-level exposures to inorganic arsenic primarily in drinking water (approximately <150 mg/L). Based on the relevant epidemiological studies with individual-level data, a threshold level for inorganic arsenic in the drinking water for these cancers is estimated to be around 100 mg/L, with strong evidence that it is between 50 and 150 mg/L, consistent with the value calculated based on mechanistic, in vitro and in vivo investigations. This evaluation provides an alternative mode of action-based approach for assessing health-protective levels for oral arsenic exposure based on the collective in vitro, in vivo, and human evidence rather than the use of a linear low-dose extrapolation based on default assumptions and theories.

Dose-Response Analysis of Exposure to Arsenic in Drinking Water and Risk of Skin Lesions: A Systematic Review of the Literature

“…29 Our analysis was restricted to a linear, non-threshold model, and did not address other dose-response relations. While non-linear models have been proposed to explain the association between arsenic exposure and prevalence of skin lesions, 5 we selected the linear model because it represents a more conservative approach, and it is adopted by regulatory authorities such as EPA for carcinogenic effects. 30 Furthermore, we based on analysis on average (lifetime) exposure, despite the fact that other aspects of exposure such as duration peaks are additional important components of arsenic toxicity.…”

“…3 Exposure to high levels of arsenic in drinking water has been associated with increased occurrence of skin lesions, including alteration of pigmentation and keratosis (Chen et al, 1997). [4][5][6] Hyperpigmentation (melanosis) consists of diffuse dark-brown or blackish areas on the skin of the neck, trunk, or extremities, as well as oral mucosa, and diffuse or spotted pigmentation on the trunk and other parts of the skin. Hypopigmentation (leukomelanosis) is characterized by whitish patches, also referred to as raindrop pigmentation.…”

Micro-RNAs: Crossroads between the Exposure to Environmental Particulate Pollution and the Obstructive Pulmonary Disease

“…As exposure is also associated with a low expression of peroxisome proliferator-activated receptor gamma resulting in a decrease of sensitization of insulin, one of the mechanisms accounting for induction of diabetes mellitus [ 44 , 45 ]. The carcinogenic effect of As has been recognized [ 46 , 47 ]. An in vitro study revealed that even low doses of As induced DNA damage (strand breakage and oxidative stress) [ 48 ].…”

Prostate Cancer Incidence in U.S. Counties and Low Levels of Arsenic in Drinking Water

“…Trivalent arsenic tends to show cytotoxicity at tissue concentrations in the µM range (> 0.1-10.0 µM (7.5-750 µg/L) [29], while pentavalent methylated arsenic is only toxic in the mM range (i.e., at >75 mg/L or >75,000 µg/L) [30]. Thus, a cellular concentration of >0.1 ug/L (7.5 ug/L) has been considered to be a reasonable estimate for the minimum cellular concentration required for obtaining a biological effect, which may be either adaptive or toxic [31]. Effects of arsenic at low concentrations on the order of 0.1 uM (7.5 ug/L) appear to be adaptive, while concentrations above 1 uM (75 ug/L) are clearly cytotoxic [32].…”

“…Effects of arsenic at low concentrations on the order of 0.1 uM (7.5 ug/L) appear to be adaptive, while concentrations above 1 uM (75 ug/L) are clearly cytotoxic [32]. Urinary levels of >0.1 uM (>7.5 ug/L) trivalent arsenic in humans are estimated to be associated with drinking water arsenic levels of 50-100 ug/L [31]. The threshold for potentially adverse cellular effects from exposure to inorganic arsenic in drinking water is thought likely to occur at urinary concentrations of trivalent arsenic above 0.2 um (15 ug/L), which corresponds to drinking water total arsenic concentrations above 65 ug/L [33].…”