Society For Risk Analysis Annual Meeting 2013

Session Schedule & Abstracts

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Common abbreviations

Symposium: Understanding Human Health Risks from Dietary Arsenic Exposure

Room: Key Ballroom 1   3:30 PM - 5:10 PM

Chair(s): Gail Charnley

Sponsored by DRSG

M4-A.1  15:30  Dietary exposure to inorganic arsenic from food in general and rice in particular. . Fitzpatrick S*, Carrington C; US Food and Drug Administration

Abstract: Given its widely appreciated toxic properties, arsenic in food has always been an important topic in food safety. It has also long been known that the organic species of arsenic in seafood is far less toxic than inorganic arsenic in food or water. However, modern chemical analytical methodology has led to the realization that there are many different forms of arsenic in food that a different toxicological properties. At the very least, there are three major categories of arsenic; inorganic arsenic species that are the most toxic, methylated arsenic species that are moderately toxic, and arsenic complexes that are practically nontoxic. While arsenic complexes are the predominant form in fish, and inorganic arsenic is the predominant form in drinking water, arsenic in most foods are comprised of a combination of inorganic and methylated species. Recent survey work conducted by the USFDA as well as other agencies indicates that while most foods have some inorganic arsenic at a relatively constant level, most of the variation in total arsenic concentrations is attributable to the presence of methylated arsenic species in highly varying amounts. In addition to considering the chemical form of arsenic in food, dietary exposure assessments must be tailored to the temporal component of the toxicological evaluation and to the individuals or populations that consume a particular food. Thus, while per capita averages of lifetime intake may serve well as characterizations of public health for some health endpoints (e.g. lifetime cancer risk), risk estimates intended to inform individual consumers are better served by the use of exposure estimates that are based on frequency of consumption. Although drinking water and smoking can also be dominant sources of exposure for some people, the major source of exposure to inorganic arsenic in the United States in the diet. In particular, rice can be the principle source of exposure in individuals and populations who are frequent consumers.

M4-A.2  15:50  Metabolism and the toxicity of arsenic. Thomas D*; US EPA

Abstract: Chronic exposure to inorganic arsenic in environmental and occupational settings has been associated with increased cancer risk. Exposure to inorganic arsenic is also strongly implicated as a causative factor for a number of non-cancer health effects. Ingested or inhaled arsenic undergoes extensive biotransformation. In humans and many other species, inorganic arsenic and its mono- and di-methylated metabolites are excreted in urine after exposure to inorganic arsenic. Enzymatically catalyzed formation of methylated metabolites of arsenic produces an array of metabolites that contain arsenic in either the trivalent or pentavalent oxidation state. Production of methylated metabolites containing trivalent arsenic is problematic because these species are highly reactive. These metabolites are more potent cytotoxins and genotoxins than inorganic arsenic. Capacity to activate arsenic by methylation is influenced by a variety of biological and behavioral factors. For example, interindividual variation in genotypes for arsenic (+3 oxidation state) methyltransferase affects the arsenic methylation phenotype and disease susceptibility phenotypes. Although most studies have focused on characterization of exposure in populations that consume drinking water containing inorganic arsenic, in some cases food can be a significant source of exposure to this metalloid. In foods, arsenic can be present in inorganic or methylated forms or in complex organic forms. Linkages among the metabolism of these arsenicals have not been elucidated, although they may be important to assessing aggregate exposure to this toxin. (This abstract does not reflect US EPA policy.)

M4-A.3  16:10  A common mode of action for arsenical toxicity. Cohen SM*; University of Nebraska Medical Center

Abstract: Inorganic arsenic increases the risk of cancer in humans, primarily of the urinary bladder, skin, and lung. Systematic investigation of the mode of action of urinary bladder carcinogenesis in rats and mice strongly supports a mode of action involving generation of reactive trivalent arsenicals which bind to sulfhydryl groups of critical proteins in the target cells, leading to cytotoxicity and consequent regenerative proliferation, increasing the risk of cancer. Arsenicals are not DNA reactive. Evidence for indirect genotoxicity indicates that this only occurs at extremely high concentrations in vitro or in vivo. Intracellular inclusions that occur in mice and humans, similar to those observed with other metals, have been mistaken for micronuclei in a variety of epidemiology studies. Although the evidence for cytotoxicity and regenerative proliferation as the mode of action is strongest for the urinary bladder, evidence is accumulating that a similar process occurs in the lung and skin, and is likely for other epithelial cell systems and for other, noncancer effects. This mode of action is consistent with a nonlinear dose response with a threshold. In rodents, the no effect level is 1 ppm of the diet or drinking water, and in vitro the no effect level is greater than 0.1 µM trivalent arsenic. Administration of inorganic arsenic is necessary above doses of 1 ppm to generate urinary or tissue concentrations above 0.1 µM. In effect, arsenicals produce a preneoplastic lesion, toxicity and cell death with regenerative proliferation, leading to increased risk of cancer if continued over time. This mode of action in animals is consistent with inorganic arsenic epidemiology and other studies in humans for these cell types. Reaction of trivalent arsenicals with critical sulfhydryl groups in target cells is the basis for inorganic arsenic toxicity for non-cancer and cancer effects.

M4-A.4  16:30  A risk assessment approach for inorganic arsenic that considers its mode of action. Clewell HJ*, Gentry PR, Yager JW; Hamner Institutes for Health Sciences, RTP, NC, ENVIRON International, Monroe, LA, and University of New Mexico, Albuquerque, NM

Abstract: Despite the absence of a complete understanding of mechanism(s) underlying the carcinogenicity and toxicity of inorganic arsenic, an alternative to the default linear extrapolation approach is needed that is more consistent with the available evidence suggesting a nonlinear dose-response. Contributory factors to the mode of action for arsenic carcinogenesis include DNA repair inhibition under conditions of oxidative stress, inflammatory and proliferative signaling, leading to a situation in which the cell is no longer able to maintain the integrity of its DNA during replication. It has been suggested that the dose-response for cancer risk assessments could be based on quantitation of molecular endpoints, or “bioindicators” of response, selected on the basis of their association with obligatory precursor events for tumorigenesis (Preston, 2002). We have applied this approach to inorganic arsenic using benchmark dose (BMD) modeling of gene expression changes in human target cells (uroepithelial cells) treated with arsenic in vitro. The BMDs for cellular gene expression changes related to the carcinogenic mode of action for arsenic were used to define the point of departure (POD) for the risk assessment. The POD was then adjusted based on data for pharmacokinetic and pharmacodynamic variability in the human population.

M4-A.5  16:50  Noncancer risk assessment of epidemiological studies of arsenic and cardiovascular disease. Perez V*, Garry MR, Alexander DD, Tsuji JS; Exponent

Abstract: The U.S. Environmental Protection Agency is currently revising their 1988 noncancer and cancer risk assessments for inorganic arsenic. Cardiovascular disease (CVD) is an endpoint with considerable recent studies supporting derivation of a non-cancer reference dose (RfD) for arsenic. We conducted a systematic review of the epidemiologic literature through March 2013 for scientific evidence that may support an RfD specific to CVD. Eleven cohort and case-control studies (Taiwan, Bangladesh, and China) assessing the effect of water arsenic at levels <100 parts per billion (ppb) were the main focus for the estimation of a dose-response relationship in the region of lowest- and no-observed-adverse-effect levels (LOAELs and NOAELs, respectively). Although the six U.S. studies were limited to ecologic or cross-sectional study designs, they were included because of their relevant target population. Consistent dose-response relationships were not evident at exposure levels <100 ppb (arsenic water concentration). A prospective cohort study (Chen, 2011) from Bangladesh provided the strongest evidence for a candidate RfD based on mortality from ischemic heart disease and other heart diseases combined. The point of departure (POD) for a NOAEL based on arsenic in water was 100 ppb based on all subjects (smoking-adjusted). PODs ranged from 0.0085-0.0094 mcg/kg-day for an inorganic arsenic dose from water and diet. Application of an uncertainty factor resulted in an RfD for CVD of 0.003 mg/kg-day. Caution should be exercised in extrapolating from populations with different lifestyles and factors to the United States. However, the Bangladesh population is likely more susceptible to arsenic-related health effects compared with the general U.S. population, thereby justifying a relatively low interindividual uncertainty factor. Similar evaluations for other potential noncancer endpoints can be conducted as a part of the overall RfD development.

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