Daniel L. Sudakin

Trichothecenes in the environment: relevance to human health

Trichothecenes are agriculturally important mycotoxins of relevance to human health. Fungi capable of producing trichothecenes can be found throughout the world, and include certain species of Fusarium, Myrothecium, and Stachybotrys. The production of mycotoxins by these toxigenic species is determined by genetic factors and the environmental conditions of their growth. The environmental fate of trichothecenes may be affected by other microorganisms that can detoxify them. Deoxynivalenol and T-2 toxin are examples of trichothecenes that are detectable as natural and unavoidable contaminants of certain agricultural commodities as well as commercial foods. Current estimates of dietary exposure to deoxynivalenol and T-2 toxin are below thresholds for adverse effects that have been reported in experimental animal studies, although historical epidemics of human illness have rarely been described in association with consumption of food derived from heavily contaminated grains. The toxicodynamic properties of trichothecenes include inhibition of protein synthesis and immunomodulatory effects. Very little information is available relating to their toxicokinetics and toxicodynamics in humans. While there is general agreement that the diet represents an important source of human exposure to trichothecenes, risk assessment from non-dietary routes of exposure is complicated by the limited epidemiological data that are currently available.

DEET: A Review and Update of Safety and Risk in the General Population

Abstract The emergence of West Nile Virus (WNV) in North America has resulted in increased public awareness and utilization of insect repellents containing N,N‐diethyl‐m‐toluamide (DEET) in the prevention of mosquito‐borne disease. Regulatory reassessments in North American countries have recently been completed for insect repellents containing DEET as active ingredient, resulting in labeling changes intended to minimize unnecessary exposure to special populations, including children. This article describes those changes, and summarizes more recent data relating to the pharmacokinetics, toxicology, and epidemiology of adverse effects associated with DEET in humans.

The spatial epidemiology of cocaine, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) use: a demonstration using a population measure of community drug load derived from municipal wastewater.

AIMS To determine the utility of community-wide drug testing with wastewater samples as a population measure of community drug use and to test the hypothesis that the association with urbanicity would vary for three different stimulant drugs of abuse. DESIGN AND PARTICIPANTS Single-day samples were obtained from a convenience sample of 96 municipalities representing 65% of the population of the State of Oregon. MEASUREMENTS Chemical analysis of 24-hour composite influent samples for benzoylecgonine (BZE, a cocaine metabolite), methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The distribution of community index drug loads accounting for total wastewater flow (i.e. dilution) and population are reported. FINDINGS The distribution of wastewater-derived drug index loads was found to correspond with expected epidemiological drug patterns. Index loads of BZE were significantly higher in urban areas and below detection in many rural areas. Conversely, methamphetamine was present in all municipalities, with no significant differences in index loads by urbanicity. MDMA was at quantifiable levels in fewer than half the communities, with a significant trend towards higher index loads in more urban areas. CONCLUSION; This demonstration provides the first evidence of the utility of wastewater-derived community drug loads for spatial analyses. Such data have the potential to improve dramatically the measurement of the true level and distribution of a range of drugs. Drug index load data provide information for all people in a community and are potentially applicable to a much larger proportion of the total population than existing measures.

Pyrethrin and pyrethroid exposures in the United States: a longitudinal analysis of incidents reported to poison centers

IntroductionCiting the Food Quality Protection Act, the US Environmental Protection Agency (EPA) decided to phase out and eliminate organophosphate insecticide use in residential environments. The phase out process spanned from 2000 to 2005, and it may have resulted in increased consumer use of insecticides containing other active ingredients. This study utilized data from the national Poison Control Center to assess possible changes in exposure incidents involving pyrethrin and pyrethroid insecticides during the phase out of organophosphates from residential uses.MethodsWe extracted pyrethrin and pyrethroid insecticide exposure data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) annual reports from 2000 to 2005. We examined pyrethrin and pyrethroid incidents by total exposures for each year, and we stratified exposures by age range, reason, number of cases treated in a health care facility, and medical outcome. Cases were examined as a proportion of all insecticide exposures. We calculated the annual incidence rates for exposures involving pyrethrin and pyrethroid insecticides of the population served.ResultsPyrethrin and pyrethroid exposures increased annually in number and as a percentage of all insecticide exposure incidents. The increase in cases was observed for all age categories and exposure reasons. A statistically significant correlation was observed between advancing years (2000–2005) and the number of pyrethrin and pyrethroid incidents (p < 01). While the number of incidents treated in a health care facility increased annually during the study period, the proportion was constant (0.185 ± 0.012) over the six-year period. During the study period, the incidence rate for pyrethrin and pyrethroid exposures increased each year. 44% of all medical outcomes data was recorded, and the majority of outcomes resulted in no symptoms (37%) or minor symptoms (53%).ConclusionTESS data showed a clear increase in cases involving pyrethrins and pyrethroids. The increase was temporally associated with the phase out of organophosphates from residential uses. In the future, medical toxicologists and poison control center personnel should be prepared to respond to an increasing number of pyrethrin and pyrethroid insecticide exposures.

Dialkyl phosphates as biomarkers of organophosphates: The current divide between epidemiology and clinical toxicology

Context. Organophosphate insecticides are widely utilized throughout the world. The cholinergic toxidrome, resulting from cholinesterase inhibition, is the clinically relevant endpoint in organophosphate poisoning. In recent years, urinary dialkyl phosphates (DAPs) have emerged as a common method of assessing exposure to organophosphates in epidemiological investigations. Using dialkyl phosphates as biomarkers of exposure to organophosphates, several recent epidemiological studies have reported associations with adverse health outcomes. The purpose of this article is to review the application and limitations of urinary DAPs as biomarkers of exposure to organophosphate insecticides. Methods. A literature search was conducted of the PubMed database, using keywords dialkylphosphate” and “dialkyl phosphate.” The scientific literature was reviewed to identify sources of dialkyl phosphate metabolites from in vivo metabolism of organophosphates, and as environmental degradation products. Epidemiological investigations were reviewed to summarize the use of use of DAPs as biomarkers in cross-sectional studies, occupational exposures, acute poisonings, and in health outcome studies. Emphasis was placed on the assessment of DAPs in the context of existing biomarker frameworks, as defined by the National Research Council. Studies were assessed for concurrent use of cholinesterase activity as a biomarker of effect, and whether a dose-response relationship could be determined between DAPs and cholinesterase depression or cholinergic effects. Results. Over 184 publications were identified, describing dialkyl phosphates and their use as biomarkers of exposure. The in vivo metabolism of organophosphates yields different DAPs, depending upon whether they undergo bioactivation or detoxification. The detection of urinary DAPs does not provide specificity with respect to the organophosphate from which they were derived, or their toxicological potency. Several recent studies documented the common presence of DAPs in residential environments and foods. Experimental studies support that DAPs have significant oral bioavailability, and undergo little to no metabolism prior to urinary excretion. Cross-sectional studies in multiple countries confirm that urinary DAPs are commonly detectable in the general population. No occupational studies were identified supporting a dose-response relationship between DAPs and significant cholinesterase inhibition. No occupational studies were identified supporting evidence of a threshold level of DAPs excretion at which clinical cholinergic signs or symptoms have been observed. Recent prospective epidemiological studies using DAPs as biomarkers have not concurrently assessed effects on cholinesterase activity, or conducted analyses that distinguish different DAPs that reflect bioactivation versus detoxification pathways. Discussion. There are numerous limitations to the use of DAPs as biomarkers of exposure. These include a lack of specificity with respect to the organophosphate from which they were derived, and a growing body of evidence that toxicologically irrelevant DAPs are commonly encountered in food and the environment. Substantial intra- and inter-day variability has been reported for dialkyl phosphate excretion in humans, which is problematic for studies that rely on single measurements to assess exposure. The toxicological distinction between different DAPs reflecting biomarkers of activation and detoxification processes has not been considered in some prospective epidemiological studies. A relationship between DAPs as biomarkers of exposure and the critical biomarker of effect, cholinesterase activity, has not been established. Conclusions. The science of exposure assessment using DAPs as biomarkers is not advancing, and this complicates the interpretation of epidemiological studies. At the current time, DAPs have very limited utility in clinical toxicology or in the risk assessment process for organophosphates. Until these limitations are addressed, the appropriate role of DAPs in the assessment of human health risks from organophosphates is unclear.

Pyrethroid insecticides : Advances and challenges in biomonitoring

Pyrethroid insecticides have a wide variety of applications throughout the world. They are structurally diverse chemicals that are synthetically derived from naturally occurring pyrethrin insecticides. Significant advances in analytical chemistry have led to the development of biomarkers of exposure to pyrethroids, and these methods are currently being applied to study exposure in the general population. This article reviews the chemistry and toxicology of pyrethroid insecticides, with an emphasis on the development of biomarkers to assess environmental exposure. Future challenges in the application of these biomarkers in epidemiological studies are explored, as is a need for improved understanding of the toxicokinetics of pyrethroids in humans.

Organophosphate Exposures in the United States: A Longitudinal Analysis of Incidents Reported to Poison Centers

The implementation of the Food Quality Protection Act of 1996 resulted in a decision by the U.S. Environmental Protection Agency to phase out and eliminate the use of organophosphate insecticides in residential environments. The phase-out and cancellation process began in the year 2000 and was complete in 2005. The purpose of this investigation was to utilize national Poison Control Center data to assess whether the risk mitigation decision had an impact on the number of incident cases involving organophosphates in the United States. Organophosphate exposure incident data were extracted from Annual Reports of the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) for the years 1995 to 2004. The number of organophosphate exposure incidents peaked at 20,135 in 1997, and declined in each subsequent year. A statistically significant decrease was observed in the average annual number of organophosphate exposure incidents when comparing data from the time periods before (1995–1999) and after (2000–2004) the commencement of the phase-out process. The decrease in organophosphate incident cases was observed for all age categories, as well as for the circumstances surrounding the exposure (unintentional and intentional exposure incidents). TESS data showed a significant decrease in incident cases involving organophosphates in association with the phase-out from residential uses. The results of this investigation are consistent with other studies that have reported that regulatory restriction of access to pesticide formulations may have a significant impact on the number of human exposure incidents.

Determination of parent and hydroxy PAHs in personal PM2.5 and urine samples collected during Native American fish smoking activities

A method was developed for the measurement of 19 parent PAHs (PAHs) and 34 hydroxylated PAHs (OH-PAHs) in urine and personal air samples of particulate matter less than 2.5 μm in diameter (PM₂.₅) using GC-MS and validated using NIST SRM 3672 (Organic Contaminants in Smokers Urine) and SRM 3673 (Organic Contaminants in Nonsmokers Urine). The method was used to measure PAHs and OH-PAHs in urine and personal PM₂.₅ samples collected from the operators of two different fish smoking facilities (tipi and smoke shed) burning two different wood types (alder and apple) on the Confederated Tribes of Umatilla Indian Reservation (CTUIR) while they smoked salmon. Urine samples were spiked with β-glucuronidase/arylsulfatase to hydrolyze the conjugates of OH-PAHs and the PAHs and OH-PAHs were extracted using Plexa and C18 solid phases, in series. The 34 OH-PAHs were derivatized using MTBSTFA, and the mixture was measured by GC-MS. The personal PM₂.₅ samples were extracted using pressurized liquid extraction, derivatized with MTBSTFA and analyzed by GC-MS for PAHs and OH-PAHs. Fourteen isotopically labeled surrogates were added to accurately quantify PAHs and OH-PAHs in the urine and PM₂.₅ samples and three isotopically labeled internal standards were used to calculate the recovery of the surrogates. Estimated detection limits in urine ranged from 6.0 to 181 pg/ml for OH-PAHs and from 3.0 to 90 pg/ml for PAHs, and, in PM₂.₅, they ranged from 5.2 to 155 pg/m(3) for OH-PAHs and from 2.5 to 77 pg/m(3) for PAHs. The results showed an increase in OH-PAH concentrations in urine after 6h of fish smoking and an increase in PAH concentrations in air within each smoking facility. In general, the PAH exposure in the smoke shed was higher than in the tipi and the PAH exposure from burning apple wood was higher than burning alder.

Regional variation in the incidence of symptomatic pesticide exposures: Applications of geographic information systems

Objective: To evaluate the epidemiology of symptomatic human pesticide exposures using poison control center data and geographic information systems. Methods: All symptomatic human pesticide exposures reported to the poison center during the period from January 1 to December 31, 2000 were included for analysis using geographic information systems. A space–time scan statistic was utilized to evaluate for clustering of symptomatic human exposures. Results: Of 322 symptomatic pesticide exposures, 297 (92%) contained spatial identifiers that could be further analyzed using geographic information systems. A spatial and temporal cluster of symptomatic pesticide exposures was identified during the period from April 1 to August 31, 2000, covering a large geographic area of eastern and predominantly rural regions of the state. The relative risk of reporting a symptomatic pesticide exposure among individuals living within this geographic area was 1.8 (log likelihood ratio=18.5, P=0.0005). Conclusions: Geographic information systems can be effectively utilized by poison control centers to study regional and temporal variation in the incidence of human pesticide exposures. With the collection of more specific spatial identifiers, geographic information systems may have many additional applications in the surveillance and prevention of pesticide and other sentinel event exposures.

Regional and temporal variation in methamphetamine-related incidents: applications of spatial and temporal scan statistics

Introduction. This investigation utilized spatial scan statistics, geographic information systems, and multiple data sources to assess spatial clustering of statewide methamphetamine-related incidents. Temporal and spatial associations with regulatory interventions to reduce access to precursor chemicals (pseudoephedrine) were also explored. Methods. Four statewide data sources were utilized including regional poison control center statistics, fatality incidents, methamphetamine laboratory seizures, and hazardous substance releases involving methamphetamine laboratories. Spatial clustering of methamphetamine incidents was assessed using SaTScan™. SaTScan™ was also utilized to assess space-time clustering of methamphetamine laboratory incidents, in relation to the enactment of regulations to reduce access to pseudoephedrine. Results. Five counties with a significantly higher relative risk of methamphetamine-related incidents were identified. The county identified as the most likely cluster had a significantly elevated relative risk of methamphetamine laboratories (RR = 11.5), hazardous substance releases (RR = 8.3), and fatalities relating to methamphetamine (RR = 1.4). A significant increase in relative risk of methamphetamine laboratory incidents was apparent in this same geographic area (RR = 20.7) during the time period when regulations were enacted in 2004 and 2005, restricting access to pseudoephedrine. Subsequent to the enactment of these regulations, a significantly lower rate of incidents (RR = 0.111, p = 0.0001) was observed over a large geographic area of the state, including regions that previously had significantly higher rates. Conclusions. Spatial and temporal scan statistics can be effectively applied to multiple data sources to assess regional variation in methamphetamine-related incidents, and explore the impact of preventive regulatory interventions.