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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. [ABSTRACT FROM AUTHOR]

Objectives: We used an environmental justice screening tool (CalEnviroScreen 1.1) to compare the distribution of environmental hazards and vulnerable populations across California communities., Methods: CalEnviroScreen 1.1 combines 17 indicators created from 2004 to 2013 publicly available data into a relative cumulative impact score. We compared cumulative impact scores across California zip codes on the basis of their location, urban or rural character, and racial/ethnic makeup. We used a concentration index to evaluate which indicators were most unequally distributed with respect to race/ethnicity and poverty., Results: The unadjusted odds of living in one of the 10% most affected zip codes were 6.2, 5.8, 1.9, 1.8, and 1.6 times greater for Hispanics, African Americans, Native Americans, Asian/Pacific Islanders, and other or multiracial individuals, respectively, than for non-Hispanic Whites. Environmental hazards were more regressively distributed with respect to race/ethnicity than poverty, with pesticide use and toxic chemical releases being the most unequal., Conclusions: Environmental health hazards disproportionately burden communities of color in California. Efforts to reduce disparities in pollution burden can use simple screening tools to prioritize areas for action.

Nanomaterials have very unique chemical and physical properties that suggest potential health hazards, but limited health and safety information exists for engineered nanomaterials. This review identifies a need for expanding efforts for addressing health and safety concerns in nanotechnology development and in nanotoxicology of engineered nanomaterials. The efforts include research to generate data for safety evaluation, toxicologic evaluation of potential human health effects, risk assessment to support risk-management decision-making, and regulations development to protect human health and the environment. The federal government's current understanding is that existing statutory authorities are adequate to address oversight of nanotechnology and its applications. On the other hand, the present review identifies weaknesses in the current research efforts and inadequacies in existing regulations. A collaborative effort involving multidisciplinary groups is a key element to address the related needs and issues. While federal agencies with regulatory responsibilities are looked upon to develop and implement sound policies and regulations to protect public health and the environment, state agencies may be required to initiate policies which rapidly incorporate new innovations and address public concerns. To address current and futures need related to nanotechnology, the responsible state agencies need to fill the information gaps and address the health and environmental issues. In California, activities have been initiated, but legislative authority and resources are required to provide risk assessment and health protection in an efficient and timely manner.

Benchmark dose methodology has been proposed as a refinement to the no observed adverse effect level (NOAEL) methods currently used for health risk assessments. We compared log-normal probit and quantal Weibull benchmark concentration (BMC) estimates using 1, 5, and 10% response incidences with inhalation toxicity NOAELs and LOAELs from 120 acute lethality data sets. These studies yielded relatively steep dose-response slopes, which in turn influenced the suitability of selecting response incidences. The mean magnitude of difference between the 95% lower confidence limits (LCLs) for 1, 5, or 10% BMCs and corresponding NOAELs was less than twofold using the probit model and less than fourfold using the Weibull model. BMC estimates at the 10% response exceeded the observed LOAEL in some cases. Maximum likelihood estimates for doses with 1, 5, or 10% responses frequently exceeded LOAELs. The probit model repeatedly gave a better fit for the data compared with the Weibull model, resulting in improved goodness of fit tests and reduced 95% confidence intervals. The 95% LCL appears to be necessary at the 1, 5, or 10% response levels in order to safely estimate a concentration below that resulting in a LOAEL., (Copyright 1999 Academic Press.)

Potency equivalency factors (PEFs) for cancer induction relative to benzo[a]pyrene have been derived for 21 polycyclic aromatic hydrocarbons (PAHs) and PAH derivatives based on a data preference scheme. PEFs have been derived only for PAHs with demonstrated carcinogenicity in bioassays. Cancer potency values and inhalation unit risks are presented for four additional carcinogenic PAHs based on expedited risk assessments conducted for California's Proposition 65. A much larger number of PAHs and PAH derivatives are considered mutagenic or genotoxic and may have limited evidence for carcinogenicity, but these compounds are not considered in this evaluation. New cancer bioassay data and possibly structure-activity analysis may indicate that additional PAHs are carcinogenic. Thus, additional PAHs may be identified as potential human carcinogens when such data become available. However, until that time the PEFs proposed for use in risk assessment were estimated only for PAHs currently classified as carcinogens.

Objective: A prospective study of civilian (nonfirefighter) smoke inhalation patients was carried out to test the hypotheses that: 1) absorption of carbon monoxide and hydrogen cyanide from smoke can be predicted by clinical examination and historical data; and, more specifically 2) a history of exposure to burning synthetic polymers is an important predictor of systemic cyanide levels., Methods: The study was conducted over a three-year period at six urban hospitals. Patients with or without burns who were exposed to smoke within five hours of hospital arrival were sampled for carboxyhemoglobin, whole blood cyanide, urine cotinine and urine creatinine. Controls consisted of a smaller group of smoking status-matched, nonsmoke-exposed burn patients., Analysis: Historical information was obtained on SMOKING status, FIRETYPE (structural vs other), MATERIAL burned (natural vs synthetic) and LAGTIME (from exposure to sampling). A smoke inhalation SCORE (0-10) was assigned to each case, based on physical examination findings and changes on chest X ray, and carboxyhemoglobin and cyanide levels were entered into various multivariate linear regression models., Results: A total of 40 cases and 9 controls were recruited, ranging in age from 15 to 92 years. Thirty-four cases were discharged alive and six expired in-hospital. Observed carboxyhemoglobin levels ranged from 1.2% to 41.6% in cases (mean 8.6%), and from 0.5 to 7.3% in controls (mean 2.9%). Observed cyanide levels ranged from nondetectable (< 0.05 micrograms/mL) to 2.79 micrograms/mL in cases (mean 0.25 micrograms/mL), and from nondetectable to 0.11 micrograms/mL in controls (mean 0.03 micrograms/mL). Among cases, linear regression models explained up to 35% of the observed variance in carboxyhemoglobin levels (p < 0.001) and up to 48% of the variance in cyanide levels (p = 0.0001)., Conclusions: SCORE was the strongest predictor of both carboxyhemoglobin and cyanide levels; LAGTIME also explained significant variance for [log-transformed] carboxyhemoglobin. Historical factors, such as FIRETYPE, MATERIAL, and SMOKING status, did not explain significant variance in most of the statistical models employed.

Study Objective: To report the occurrence of persistent respiratory disorders, including irritant-induced asthma, among adults living and working near an environmental spill of the pesticide, metam sodium, after the derailment of a tank car., Design: Retrospective clinical case series., Setting: California communities situated within one-half mile of the Sacramento River, from Mt. Shasta City to Shasta Lake., Patients: 197 adults referred to a university occupational/environmental health clinic or to a private occupational/environmental health practitioner for evaluation of health problems potentially related to the spill., Measurements and Results: History, physical examination, review of medical records, spirometry, and methacholine challenge testing revealed 20 cases of persistent irritant-induced asthma and 10 cases of persistent exacerbation of asthma., Conclusions: This is the first reported series of cases of persistent irritant-induced asthma involving both community residents and occupationally exposed individuals.

A tank car derailment in northern California in 1991 spilled metam sodium into the Sacramento River, and released its breakdown product, methyl isothiocyanate (MITC), into the air. This paper describes the risk evaluation process used. Over 240 individuals reported symptoms such as eye and throat irritation, dizziness, and shortness of breath. Reference exposure levels (RELs) for 1 hr were developed for MITC and compared to exposure concentrations. Ocular irritation in cats was the most sensitive endpoint reported. The no observed adverse effect level (NOAEL), divided by an uncertainty factor (UF) of 100, produced an REL of 0.5 ppb of MITC in air to prevent discomfort. An REL to prevent disability was estimated to be 40 ppb. An REL to prevent life-threatening injury was estimated to be 150 ppb. Measured MITC levels ranged from 0.2-37 ppb and estimated peak levels ranged from 140-1600 ppb. The usefulness of RELs for emergency planning is discussed.

Communities across the United States are examining the manufacture, use, transport, and storage of hydrogen fluoride (HF) near residential areas as a consequence of a major release of HF in Texas in 1987. Reference exposure levels for routine and accidental HF emissions are calculated using existing animal and human data. The approach employs a log-probit extrapolation of concentration-response data to the 95% lower confidence limit on the toxic concentration producing a "benchmark dose" of 1% response (TC01), called a practical threshold. Species-specific and chemical-specific adjustment factors are applied to develop exposure levels applicable to the general public. Using this method, the 1-hr reference exposure level to protect the public against any irritation from a routine emission (REL-1) is 0.7 ppm and the level to protect against severe irritation from a once-in-a-lifetime (REL-2) release is 2 ppm. This approach is compared to a modified "uncertainty factor" approach.

Cadmium and cadmium compounds are carcinogenic both by inhalation and by injection. For purposes of risk assessment, a prudent public health approach has been that, if a chemical has been demonstrated to be carcinogenic by one route, it should be considered carcinogenic by all routes. This policy has been questioned for several toxic metals including cadmium. After reviewing the literature on cadmium carcinogenicity and genotoxicity, we think that cadmium should be considered noncarcinogenic by the oral route. The bases for this decision included: (1) a database for genotoxicity of cadmium with more negative test results than positive results and with most positive results in in vitro tests, indicating that cadmium has limited genotoxicity; (2) some epidemiologic evidence of respiratory tract cancer and prostatic cancer in people occupationally exposed to airborne cadmium but no reliable evidence of gastrointestinal tract cancers in workers; and (3) a large dietary oncogenicity study in rats of cadmium chloride at several dose levels, including a maximally tolerated dose (50 ppm) in males, which showed no increase of tumors due to cadmium ingestion in all of the 19 tissues examined. The conclusion that an agent, which has been shown to be carcinogenic by one route of exposure, is not carcinogenic by a second route should be made only in the presence of robust data which indicate the lack of effect via the second route of exposure.

Since the 1920s ethylene dibromide's (EDB's) primary use has been as a scavenger of lead compounds in gasoline. Gasoline evaporation contributed to EDB emissions into the environment. In 1973, the United States Environmental Protection Agency (EPA) issued regulations to reduce the use of leaded gasoline and this has resulted in lower EDB usage and emissions. In addition, EDB has been used extensively as a fumigant since 1948. Its volatility and versatility, based on chemical and biocidal properties, led to its use as a soil sterilant, as a spot fumigant of grain milling machinery, and as a control agent in grain, fruit and vegetable infestations. In 1977 the EPA began a review of EDB's pesticidal uses which eventually led to its cancellation for most agricultural applications. Disposal of EDB and contamination of water supplies remain major environmental concerns. EDB can be absorbed via the dermal, oral and inhalation routes. It appears to be metabolized in vivo by an oxidative pathway (cytochrome P-450) and a conjugation pathway (glutathione S-transferase). The metabolites play an important role in exerting its toxicity. Few human poisonings have been reported from either acute or chronic exposure. However, EDB is irritating to the skin and eyes. Limited information indicates that EDB can damage the liver and kidneys following extensive or prolonged exposure. The genotoxicity of EDB has been clearly demonstrated. It binds to DNA in vivo and in vitro, and a DNA adduct has been identified. EDB has been shown to be mutagenic in numerous bacterial assays, in fungi, in plants, in insects, and in mammalian cell culture. Some evidence indicates that EDB can cause sister chromatid exchange and chromosomal aberrations. EDB is a reproductive toxin, but it does not appear to be teratogenic. It has been shown to affect spermatogenesis in rats, bulls and rams and to affect fertility in fowl. Human studies indicate that EDB exposure may harm sperm and decrease fertility. The toxic effect of greatest concern that may result from EDB exposure is cancer. In rats and mice, EDB produced tumors at the application site and at distant sites. When given orally, EDB has produced tumors in the forestomach, lung, and the circulatory system. When administered by inhalation, EDB produced tumors in the nasal cavity, lung, and the circulatory system. Dermal application of EDB produced skin and lung tumors. Analyses of risks from EDB exposure have focused on potential carcinogenic effects. Initial risk estimates, based on animal studies, indicated that citrus workers had essentially a 100% chance of contracting cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Mice were exposed via inhalation to high concentrations of either dichloromethane (168 mg/l) or carbon tetrachloride (134.3 mg/l). The mice were tested for learning ability using a passive-avoidance conditioning task. Exposed animals were found to have a significantly decreased ability to learn when compared with controls. The 3-wk-old mice were more affected than the 5-wk-old and the 8-wk-old mice. The exposed animals were indistinguishable from controls in terms of motor activity, weight gain, and absence of analgesia.

Hexavalent chromium was identified by California as a toxic air contaminant (TAC) in January 1986. The California Department of Health Services (CDHS) concurred with the findings of the International Agency for Research on Cancer that there is sufficient evidence to demonstrate the carcinogenicity of chromium in both animals and humans. CDHS did not find any compelling evidence demonstrating the existence of a threshold with respect to chromium carcinogenesis. Experimental data was judged inadequate to assess potential human reproductive risks from ambient exposures. Other health effects were not expected to occur at ambient levels. The theoretically increased lifetime carcinogenic risk from a continuous lifetime exposure to hexavalent chromium fell within the range 12-146 cancer cases per nanogram hexavalent chromium per cubic meter of air per million people exposed, depending on the potency estimate used. The primary sources found to contribute significantly to the risk of exposure were chrome platers, chromic acid anodizing facilities and cooling towers utilizing hexavalent chromium as a corrosion inhibitor. Evaluation of genotoxicity data, animal studies and epidemiological studies indicates that further consideration should be given to the potential carcinogenicity of hexavalent chromium via the oral route.

The possibility of accidental industrial chemical releases has generated considerable recent attention. One area requiring research for emergency planning is the development of safe exposure concentrations for the public in the event of an inadvertent release. The United States Environmental Protection Agency (EPA) has established a list of extremely hazardous substances and suggested that the toxicity ranking for 92 hazardous materials could be based on the "immediately dangerous to life or health" (IDLH) values developed by the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA). Eighty-four compounds with IDLH values for which published toxicologic data were available were reviewed to assess the appropriateness of applying such values to accidental release situations. When compared with 30-min animal median lethal concentrations (LC50s), 18 of the IDLHs reviewed were in the same range as lethal levels for animals. For 45 compounds the IDLH values were comparable to concentrations producing severe toxic effects (specifically, unconsciousness, incapacitation, or intolerable irritation). Where available, emergency planning guidelines for the military were compared to IDLHs, and in all 31 cases, the IDLHs exceeded the military exposure guidelines. Twenty compounds also were found to pose a potential cancer risk according to common regulatory guidelines, even under the assumption of a single, 30-min exposure at the IDLH concentration. In addition, the high degree of variability (four orders of magnitude) in the relationship of IDLH values to outcomes of lethality or severe toxicity suggests that the use of IDLH values as emergency planning guidelines for accidental releases is questionable.(ABSTRACT TRUNCATED AT 250 WORDS)

An inhalation system was designed and constructed for acute nose exposure of mice to methyl bromide. Animals were exposed for 1 h to concentrations ranging from 0.87 to 5.93 mg/l. Mice exposed to concentrations up to 1.72 mg/l did not exhibit any indication of developing a toxic response. Animals exposed to concentrations to 2.20 and 2.70 mg/l exhibited significantly decreased lung and liver weights when compared to controls. Animals exposed to concentrations above 3.50 mg/l exhibited kidney lesions. At concentrations of 3.82 mg/l and above, animals exhibited abnormal clinical signs, weight loss, and mortality. In addition, at 4.70 mg/l, a liver lesion was observed. At concentrations above 5.77 mg/l, pathological changes were observed in the color and a decreased motor coordination was evident. Methyl bromide exposures of up to 3.82 mg/l did not affect the ability of mice to recall a single-task passive-avoidance test. The 1-h LC50 of methyl bromide in mice via inhalation was determined to be 4.68 mg/l (approximately 1200 ppm). The dose-response curve was quite steep and the LC10 to LC90 range of mortality was contained within a doubling of concentration.