Michael R. Garry

Low-level arsenic exposure and developmental neurotoxicity in children: A systematic review and risk assessment.

UNLABELLED Risk assessments of arsenic have focused on skin, bladder, and lung cancers and skin lesions as the sensitive cancer and non-cancer health endpoints, respectively; however, an increasing number of epidemiologic studies that can inform risk assessment have examined neurodevelopmental effects in children. We conducted a systematic review and risk assessment based on the epidemiologic literature on possible neurodevelopmental effects at lower arsenic exposures. Twenty-four cross-sectional, case-control, and cohort studies were identified that report on the association between low-level arsenic exposure (i.e., largely <100 μg/L of arsenic in drinking water) and neurological outcomes in children. Although the overall evidence does not consistently show a causal dose-response relationship at low doses, the most rigorously conducted studies from Bangladesh indicate possible inverse associations with cognitive function, predominantly involving concurrent arsenic exposure as measured by biomarkers (i.e., arsenic in urine or blood) and raw verbal test scores at ages 5-11 years. Issues such as non-comparability of outcome measures across studies; inaccuracies of biomarkers and other measures of inorganic arsenic exposure; potential effect modification by cultural practices; insufficient adjustment for nutritional deficiencies, maternal IQ, and other important confounders; and presence of other neurotoxicants in foreign populations limit generalizability to U.S. POPULATIONS Of the few U.S. studies available, the most rigorously conducted study did not find a consistent dose-response relationship between arsenic concentrations in tap water or toenails and decrements in IQ scores. Assuming that the strongest dose-response relationship from the most rigorous evidence from Bangladesh is generalizable to U.S. populations, possible reference doses were estimated in the range of 0.0004-0.001 mg/kg-day. These doses are higher than the U.S. Environmental Protection Agency reference dose for chronic lifetime exposure, thus indicating protectiveness of the existing value for potential neurotoxicity in children. This reference dose is undergoing revision as EPA considers various health endpoints in the reassessment of inorganic arsenic health risks.

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

BACKGROUND Shortened and bent long bones and bent scapulae are sometimes reported in fetuses with wavy ribs (Carney and Kimmel, ). Wavy ribs are typically seen in the presence of maternal and developmental toxicity, are transient and reversible postnatally, and are considered to be variations rather than malformations. METHODS We further assessed the literature cited in Kimmel and Carney () as well as papers published since then to determine under what conditions bent long bones in the absence of gross limb defects and bent scapulae were reported and whether information was available on the transient or permanent nature of these effects. RESULTS Long bone and/or scapular changes almost always occurred at a lower incidence than wavy ribs. In every case, maternal and fetal toxicity occurred at the same dose levels. In a few studies, pups were followed sequentially after birth and bent long bones and scapulae were transient in nature and appeared normal by the time of weaning. Rabbits were much less likely to show wavy ribs or long bone and scapular changes at birth, even in the presence of severe maternal and fetal toxicity. This species difference may be due in part to the great increase in bone mass and remodeling that occurs during the first few postnatal weeks in rodents, but which takes place during the longer fetal period in rabbits. CONCLUSION Our conclusion from this review is that bent long bones and scapulae, like wavy ribs, appear to be secondary to maternal and developmental toxicity, are transient, and like wavy ribs should be considered variations rather than malformations.

Review of Information Resources to Support Human Exposure Assessment Models

Efforts to model human exposures to chemicals are growing more sophisticated and encompass increasingly complex exposure scenarios. The scope of such analyses has increased, growing from assessments of single exposure pathways to complex evaluations of aggregate or cumulative chemical exposures occurring within a variety of settings and scenarios. In addition, quantitative modeling techniques have evolved from simple deterministic analyses using single point estimates for each necessary input parameter to more detailed probabilistic analyses that can accommodate distributions of input parameters and assessment results. As part of an overall effort to guide development of a comprehensive framework for modeling human exposures to chemicals, available information resources needed to derive input parameters for human exposure assessment models were compiled and critically reviewed. Ongoing research in the area of exposure assessment parameters was also identified. The results of these efforts are summarized and other relevant information that will be needed to apply the available data in a comprehensive exposure model is discussed. Critical data gaps in the available information are also identified. Exposure assessment modeling and associated research would benefit from the collection of additional data as well as by enhancing the accessibility of existing and evolving information resources.

In utero arsenic exposure in mice and early life susceptibility to cancer

In its review of the U.S. Environmental Protection Agencys toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses.

Developing Risk-Based Target Concentrations for Carcinogenic Polycyclic Aromatic Hydrocarbon Compounds Assuming Human Consumption of Aquatic Biota

As part of the remediation process at a former creosote-handling facility in Washington, target groundwater concentrations were developed as goals for the planned cleanup efforts. Considering state regulatory requirements and site-specific conditions, these concentrations were established to protect surface water in the lake adjacent to the site. These risk-based values were calculated assuming that chemicals will (1) be transported in groundwater, (2) discharge into the lake, and (3) be taken up by aquatic organisms that may be consumed by humans. Among the primary chemicals driving remediation decisions at this site are carcinogenic polycyclic aromatic hydrocarbon (cPAH) compounds, which have limited environmental mobility and are metabolized by many types of potentially edible aquatic organisms. This work included assessing the validity for cPAH compounds of the required default regulatory assumptions and deriving alternative risk-based concentrations. These analyses focused on factors that would modify the generic assumption regarding bioconcentration of cPAH compounds in aquatic biota and influence bioavailability of cPAH compounds to humans consuming the biota. Modifications based on these factors and the use of toxicity equivalency factors resulted in alternative risk-based concentrations for individual cPAH compounds that ranged from approximately 7 to 700 times greater than the default value of 0.03 w g/L.

Fish consumption as a driver of risk‐management decisions and human health–based water quality criteria

The use and interpretation of fish consumption surveys and interviews, the application of fish consumption rates for sediment evaluation and cleanup, and the development of human health water quality criteria (HH WQC) are complex and interrelated issues. The present article focuses on these issues using examples from the United States, although the issues may be relevant for other countries. Some key considerations include the fact that there are many types of fish consumption surveys (e.g., 24-h recall surveys, food frequency questionnaires, creel surveys), and these surveys have different advantages and limitations. Identification of target populations for protection, identification of the species and quantities of fish consumed, and determination of bioaccumulation assumptions are important factors when developing water quality and sediment screening levels and standards. Accounting for the cultural importance of fish consumption for some populations is an even more complex element. Discussions about HH WQC often focus only on the fish consumption rate and may not have broad public input. Some states are trying to change this through extensive public participation efforts and use of probabilistic approaches to derive HH WQC. Finally, there are limits to what WQC can achieve. Solutions beyond the establishment of WQC that target toxics reduction from other sources may provide the greatest improvements to water quality and reductions in human health risks in the future.

Application of a weight of evidence approach to evaluating risks associated with subsistence caribou consumption near a lead/zinc mine

Overland transport of ore concentrate from the Red Dog lead/zinc mine in northwest Alaska to its seaport has historically raised concerns among local subsistence users regarding the potential impacts of fugitive dust from the operation, including the potential uptake of metals into caribou meat. Caribou are an integral part of life for northern Alaska Natives for both subsistence and cultural reasons. The Western Arctic caribou herd, whose range includes the Red Dog mine, transportation corridor, and port site, sometimes overwinter in the vicinity of mine operations. A weight of evidence approach using multiple lines of evidence was used to evaluate potential risks associated with subsistence consumption of caribou harvested near the road and mine. Data from a long-term caribou monitoring program indicate a lack of consistent trends for either increasing or decreasing metals concentrations in caribou muscle, liver, and kidney tissue. Lead, cadmium, and zinc from all tissues were within the range of reference concentrations reported for caribou elsewhere in Northern Alaska. In addition, a site use study based on data from satellite-collared caribou from the Western Arctic Herd showed that caribou utilize the area near the road, port, and mine approximately 1/20th to 1/90th of the time assumed in a human health risk assessment conducted for the site, implying that risks were significantly overestimated in the risk assessment. The results from multiple lines of evidence consistently indicate that fugitive dust emissions from Red Dog Operations are not a significant source of metals in caribou, and that caribou remain safe for human consumption.

Utilizing a Combination of TGA and GC-MS to Estimate Health-Based Risks from Off-Gassed Volatile Compounds

Off-gassed compounds emitted from various materials can, in some instances, present health risks. In order to assess the potential health risks, off-gassed compounds must be identified, quantified, and evaluated relative to known health-based exposure guidance levels. We present a simple screening method for doing this that combines thermogravimetric analysis with thermal desorption–gas chromatography–mass spectrometry. The masses of particular volatile compounds are estimated over the course of a short-term, acute exposure. Assumptions (or measurements) of a room size can be used to convert these mass estimates to estimated concentrations, which can then be compared with readily available health-based exposure thresholds.