Gina Solomon

TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

The 2006 California heat wave: impacts on hospitalizations and emergency department visits.

Background Climate models project that heat waves will increase in frequency and severity. Despite many studies of mortality from heat waves, few studies have examined morbidity. Objectives In this study we investigated whether any age or race/ethnicity groups experienced increased hospitalizations and emergency department (ED) visits overall or for selected illnesses during the 2006 California heat wave. Methods We aggregated county-level hospitalizations and ED visits for all causes and for 10 cause groups into six geographic regions of California. We calculated excess morbidity and rate ratios (RRs) during the heat wave (15 July to 1 August 2006) and compared these data with those of a reference period (8–14 July and 12–22 August 2006). Results During the heat wave, 16,166 excess ED visits and 1,182 excess hospitalizations occurred statewide. ED visits for heat-related causes increased across the state [RR = 6.30; 95% confidence interval (CI), 5.67–7.01], especially in the Central Coast region, which includes San Francisco. Children (0–4 years of age) and the elderly (≥ 65 years of age) were at greatest risk. ED visits also showed significant increases for acute renal failure, cardiovascular diseases, diabetes, electrolyte imbalance, and nephritis. We observed significantly elevated RRs for hospitalizations for heat-related illnesses (RR = 10.15; 95% CI, 7.79–13.43), acute renal failure, electrolyte imbalance, and nephritis. Conclusions The 2006 California heat wave had a substantial effect on morbidity, including regions with relatively modest temperatures. This suggests that population acclimatization and adaptive capacity influenced risk. By better understanding these impacts and population vulnerabilities, local communities can improve heat wave preparedness to cope with a globally warming future.

Airborne Mold and Endotoxin Concentrations in New Orleans, Louisiana, after Flooding, October through November 2005

Background The hurricanes and flooding in New Orleans, Louisiana, in October and November 2005 resulted in damp conditions favorable to the dispersion of bioaerosols such as mold spores and endotoxin. Objective Our objective in this study was to assess potential human exposure to bioaerosols in New Orleans after the flooding of the city. Methods A team of investigators performed continuous airborne sampling for mold spores and endotoxin outdoors in flooded and nonflooded areas, and inside homes that had undergone various levels of remediation, for periods of 5–24 hr during the 2 months after the flooding. Results The estimated 24-hr mold concentrations ranged from 21,000 to 102,000 spores/m3 in outdoor air and from 11,000 to 645,000 spores/m3 in indoor air. The mean outdoor spore concentration in flooded areas was roughly double the concentration in nonflooded areas (66,167 vs. 33,179 spores/m3; p < 0.05). The highest concentrations were inside homes. The most common mold species were from the genera of Cladosporium and Aspergillus/Penicillium; Stachybotrys was detected in some indoor samples. The airborne endotoxin concentrations ranged from 0.6 to 8.3 EU (endo-toxin units)/m3 but did not vary with flooded status or between indoor and outdoor environments. Conclusions The high concentration of mold measured indoors and outdoors in the New Orleans area is likely to be a significant respiratory hazard that should be monitored over time. Workers and returning residents should use appropriate personal protective equipment and exposure mitigation techniques to prevent respiratory morbidity and long-term health effects.

Manganese in the U.S. gasoline supply

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese compound recently approved for use in the United States as a gasoline additive. MMT use is expected to increase. This Commentary analyzes the impact of MMT use on population exposure to manganese, the health effects associated with manganese exposure, and the possibility that MMT use will lead to toxicity in the population. Although MMT use would result in only a small increment in most peoples manganese exposure, certain populations will be disproportionately exposed. Although manganese is an essential nutrient at low levels, high-level manganese exposure leads to a characteristic severe nervous system toxicity. Pulmonary toxicity also occurs at high levels of exposure, and developmental toxicity to fetuses is an important concern based on more limited data. Selected subpopulations may be especially susceptible to the toxic effects of manganese. The critical question is whether the additional population exposure to manganese that would result from widespread MMT use would lead to toxic effects. Currently available evidence does not permit firm conclusions. Common sense and prudence therefore dictate that MMT not be used until further data are available and its safety is confirmed. Several measures are recommended to address the impending use of MMT in the U.S. gasoline supply.

Health Effects of the Gulf Oil Spill

The oil spill in the Gulf of Mexico poses direct threats to human health from inhalation or dermal contact with the oil and dispersant chemicals, and indirect threats to seafood safety and mental health. Physicians should be familiar with health effects from oil spills to appropriately advise, diagnose, and treat patients who live and work along the Gulf Coast or wherever a major oil spill occurs.

Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Background Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an “adverse effect” in the context of hazard identification and risk assessment. Objectives Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. Discussion Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. Conclusions For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.

Stillbirth after occupational exposure to N-methyl-2-pyrrolidone. A case report and review of the literature.

N-methyl-2-pyrrolidone is a solvent that is increasingly used in a variety of industries, including petroleum refining, microelectronics, pesticide formulation, and veterinary medicine. Animal studies have demonstrated fetotoxic effects after maternal exposure to doses that have minimal to no adverse effect on the mothers. The fetotoxicity comprises resorption, stillbirth, and low birthweight and delayed ossification in surviving young. We report a human case of intrauterine growth retardation followed by fetal demise at 31 weeks gestation. The mother was a laboratory worker with no other apparent risk factors, who sustained occupational exposure to N-methyl-2-pyrrolidone throughout the first trimester of pregnancy. Laboratory work and solvent exposure have both previously been associated with adverse reproductive outcomes. Laboratories and other industries that use suspected reproductive toxins should have reproductive health policies in place that allow for decision-making based on toxicologic review, exposure assessment, and medical evaluation. These policies should allow for voluntary removal of prospective parents until environmental assessment and controls are instituted.

Seafood contamination after the BP Gulf oil spill and risks to vulnerable populations: a critique of the FDA risk assessment.

Background: The BP oil spill of 2010 resulted in contamination of one of the most productive fisheries in the United States by polycyclic aromatic hydrocarbons (PAHs). PAHs, which can accumulate in seafood, are known carcinogens and developmental toxicants. In response to the oil spill, the U.S. Food and Drug Administration (FDA) developed risk criteria and established thresholds for allowable levels [levels of concern (LOCs)] of PAH contaminants in Gulf Coast seafood. Objectives: We evaluated the degree to which the FDA’s risk criteria adequately protect vulnerable Gulf Coast populations from cancer risk associated with PAHs in seafood. Discussion: The FDA LOCs significantly underestimate risk from seafood contaminants among sensitive Gulf Coast populations by failing to a) account for the increased vulnerability of the developing fetus and child; b) use appropriate seafood consumption rates; c) include all relevant health end points; and d) incorporate health-protective estimates of exposure duration and acceptable risk. For benzo[a]pyrene and naphthalene, revised LOCs are between two and four orders of magnitude below the level set by the FDA. Comparison of measured levels of PAHs in Gulf seafood with the revised LOCs revealed that up to 53% of Gulf shrimp samples were above LOCs for pregnant women who are high-end seafood consumers. Conclusions: FDA risk assessment methods should be updated to better reflect current risk assessment practices and to protect vulnerable populations such as pregnant women and children.

Outcomes of the California ban on pharmaceutical Lindane: clinical and ecologic impacts

Introduction There are increasing concerns over the presence and implications of pharmaceutical agents in water. In 2002, California banned pharmaceutical use of lindane because of concerns about water quality, as lindane treatment for head lice and scabies was found to be a significant factor adversely affecting wastewater quality. Objectives In this article we describe the effects the ban has had on wastewater quality, unintentional exposures, and clinical practice. This is the first time that a pharmaceutical has been outlawed to protect water quality. As such, this ban provides a rare opportunity to evaluate the possible or potential outcomes of future public health interventions aimed at reducing pharmaceutical water contamination. Methods We compiled data on lindane in wastewater treatment plant effluent for several large plants in California and one outside of California. Data on exposures to lindane were obtained from records of the California Poison Control System. We assessed the impact on clinical practice via a survey of 400 pediatricians Results Wastewater treatment plant monitoring showed that lindane declined in California after the ban. Similarly, unintentional exposure calls declined. Most physicians were aware of the ban (81%) and had used lindane previously (61%), but they did not notice any difficulties with the ban (78%). Conclusions The California experience suggests that elimination of pharmaceutical lindane produced environmental benefits, was associated with a reduction in reported unintentional exposures, and did not adversely affect head lice and scabies treatment. This ban serves as a model for governing bodies considering limits on the use of lindane or other pharmaceuticals.

Cumulative Environmental Impacts: Science and Policy to Protect Communities

Many communities are located near multiple sources of pollution, including current and former industrial sites, major roadways, and agricultural operations. Populations in such locations are predominantly low-income, with a large percentage of minorities and non-English speakers. These communities face challenges that can affect the health of their residents, including limited access to health care, a shortage of grocery stores, poor housing quality, and a lack of parks and open spaces. Environmental exposures may interact with social stressors, thereby worsening health outcomes. Age, genetic characteristics, and preexisting health conditions increase the risk of adverse health effects from exposure to pollutants. There are existing approaches for characterizing cumulative exposures, cumulative risks, and cumulative health impacts. Although such approaches have merit, they also have significant constraints. New developments in exposure monitoring, mapping, toxicology, and epidemiology, especially when informed by community participation, have the potential to advance the science on cumulative impacts and to improve decision making.