Critical Aspects of EPA's IRIS Assessment of Inorganic Arsenic Interim Report (2013) / Chapter Skim
Currently Skimming:
5 Susceptibility Factors
5 Susceptibility Factors
Pages 51-75
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 51... ...
Concerning prenatal arsenic exposure, it seems clear that all metabolites of inorganic arsenic easily cross the placenta to the fetus. Strong correlations between arsenic in maternal blood and in cord blood have been found in women exposed to arsenic-contaminated drinking water (Concha et al.
|
From page 52... ...
. The human evidence of later-life effects of low-dose early-life arsenic exposure is supported by a series of experimental studies in mice that were given drinking water that contained arsenic at 50 µg/L (mainly arsenate)
|
From page 53... ...
Although changes in DNA methylation have been observed and associated with arsenic exposure, their biologic effects and meaning at a functional level in the cell and as related to health effects are unknown. Key Considerations for the IRIS Assessment Collectively, the highly suggestive evidence that early-life exposure to arsenic, even at low concentrations, increases the risk of adverse health effects and impaired development in infancy and childhood and later in life leads the committee to suggest that the timing of exposure, particularly early-life exposure, be considered in evaluating epidemiologic studies for dose–response assessment.
|
From page 54... ...
. To date, genomewide association studies have been conducted to identify genetic risk factors for diseases as varied as age-related macular degeneration (Haines et al.
|
From page 55... ...
Further study, typically deep sequencing and the identification of functional variants, is needed before any genes can be considered as susceptibility factors. Finally, in any study of genetic contributions to arsenic metabolism, estimates of heritability are probably influenced by the degree of exposure in the underlying populations (that is, in the absence of arsenic exposure, a genetic trait cannot exhibit heritability)
|
From page 56... ...
(2011) did not find an association or evidence of effect modification between arsenic exposure and GSTO1 and O2 polymorphisms and carotid atherosclerosis but did find evidence of effect modification between a haplotype of purine nucleoside phosphoralase SNPs and wellwater arsenic.
|
From page 57... ...
Most have been candidate-gene studies that focused on arsenic-metabolism genes. A small number have also addressed whether these genes modify the relationship between inorganic arsenic exposure and health effects but only for cancer, metabolic syndrome, cardiovascular disease, and skin lesions.
|
From page 58... ...
. Liver tumors were induced in female offspring only when the in utero arsenic exposure was combined with skin application of a tumor-promoting phorbol ester, 12-Otetradecanoylphorbol-13-acetate (Waalkes et al.
|
From page 59... ...
. Another study of the influence of nutritional status on arsenic metabolism, carried out in pregnant women in Bangladesh, found only a marginal effect of plasma folate (after adjustment for the degree of arsenic exposure)
|
From page 60... ...
Because this is an emerging field of vulnerability assessment, several underlying principles and implications for quantitative risk assessment are outlined below in relation to considerations for inorganic arsenic. Chemical interactions with background disease processes may be of several types as shown in Figure 3: The disease alters chemical action by altering toxicokinetics so as to change internal dose materially.
|
From page 61... ...
creating a vulnerability to chemical effect. Interaction could also affect disease risk especially if the chemical and disease have similar upstream pathways and clinical outcomes (upward arrows)
|
From page 62... ...
. Arsenic exposure is associated with increases in plasma adhesion molecules that are indicative of endothelial dysfunction, vascular inflammation, and increased risk of cardiovascular disease (Y.
|
From page 63... ...
Evaluating the evidence of susceptibility on the basis of pre-existing disease requires sufficient disease and nondisease subjects who have well-defined arsenic exposures and assessment of arsenic-related end points. Most epidemiologic studies, however, have not evaluated differences in arsenic susceptibility, so it is difficult to evaluate the importance of the interaction between arsenic and background disease.
|
From page 64... ...
Evidence of that would ideally involve prospective studies that include assessment of a preclinical biomarker, arsenic exposure, and disease incidence over time. Without such evidence, it may still be possible to estimate the increased risk of disease (such as chronic renal disease or myocardial infarction)
|
From page 65... ...
Because smoking is still relatively common, the finding of synergism with arsenic for at least four disease outcomes will be an important consideration. Indeed, of all susceptibility factors evaluated, smoking is probably the one on which the findings at both high and low to moderate arsenic exposure were most consistent.
|
From page 66... ...
Quantitative approaches may involve separate analysis of vulnerable groups if such group-specific data are available or adjustment of the overall population response to account for specific chemical interactions or vulnerability factors. MIXTURES AND COEXPOSURES Coexposures or mixtures that include inorganic arsenic complicate the risk evaluation of arsenic in at least two ways: arsenic may interact with other agents that potentially modify the effect of arsenic, and there may be a combination effect of arsenic with other similarly acting chemicals (such as other metals)
|
From page 67... ...
However, that may be somewhat speculative given limitations in quantitative dose–response data and in the mechanistic information needed to explore such possible potentiation fully. Therefore, this is a subject worthy of mention by EPA as an additional mechanistic consideration that may help to explain some of the end points associated with arsenic exposure.
|
From page 68... ...
With respect to inorganic arsenic, it is plausible that those in pre-existing or high-risk categories for chronic diseases (such as cardiovascular disease, diabetes, and renal disease) could be more vulnerable to arsenic toxicity inasmuch as arsenic has been associated with increased risks of those conditions in at least some cases or has been shown to act on upstream biomarkers of disease risk (e.g., Wu et al.
|
From page 69... ...
. As the dose is lowered, fewer people are responsive, so statistical significance is harder to achieve, but this does not mean that the risk at low dose is zero.
|
From page 70... ...
In addition, strong data on actual systemic exposure to the various forms of arsenic after ingestion are often difficult to obtain. Identifying those data gaps and their potential effect on the ability to extrapolate to potential effects at low exposures wil be an important part of the IRIS assessment process.
|
From page 71... ...
Mode-of-action analysis is distinct from a detailed understanding of mechanism of action and places into perspective all relevant scientific data that link key events and pathways to an adverse health outcome that is consistent with the underlying biology of the target tissue. It is that aspect of mode-of-action analysis that places available data into a context that can be used to interpret vulnerability among species and among individuals so that changes in dose–response relationships in going from high to low exposures can be understood.
|
From page 72... ...
Linkage of adverse health outcomes to the key events in a mode-of-action analysis -- when coupled with exposure, metabolism, tissue accumulation of parent and metabolites, and ratelimiting steps (such as protein binding, reactive oxygen signaling, cytotoxicity, proliferation, apoptosis, receptor effects, and immune suppression) -- provides a strong hazard identification and characterization analysis.
|
From page 73... ...
Determination of the key events in an adverse-outcome pathway is in the context of the exposure and duration of exposure leading to the key intermediary steps in the pathogenesis of the health outcome. The key events must be linked in an exposure and temporal pattern for each of the steps in the pathway (cf Andersen et al.
|
From page 74... ...
DNA methylation is the most widely studied epigenetic modulation in humans and other mammals; it can influence gene silencing by directly affecting the affinity of transcription factors for their DNA binding sites. Arsenic exposure has been associated with decreased S-adenosyl methionine concentrations (and increased concentrations of S-adenosyl homocysteine)
|
From page 75... ...
Such analysis permits an unbiased use of all the available data to examine the effects of arsenic exposure and exposure duration at different doses. A mode-of-action analysis needs to be compiled for each health outcome that has been ascribed to arsenic exposure to inform the risk assessment.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.