BACKGROUND:Fluoride is a common exposure in our environment that comes from a variety of sources and is widely promoted for its dental and overall oral health benefits. Contributions to an individual's total exposure come primarily from fluoride in drinking water, food, beverages and dental products. A 2006 evaluation by the National Research Council (NRC) found support for an association between consumption of high levels of naturally occurring fluoride in drinking water and adverse neurological effects in humans and recommended further investigation. The evidence reviewed at that time was from dental and skeletal fluorosis-endemic regions of China. Since the NRC evaluation, the number and location of studies examining cognitive and neurobehavioral effects of fluoride in humans have grown considerably, including several recent North American prospective cohort studies evaluating prenatal fluoride exposure. In 2016, the National Toxicology Program (NTP) published a systematic review of the evidence from experimental animal studies on the effects of fluoride on learning and memory. That systematic review found a low-to-moderate level of evidence that deficits in learning and memory occur in non-human mammals exposed to fluoride. OBJECTIVE:To conduct a systematic review of the human, experimental animal, and mechanistic literature to evaluate the extent and quality of the evidence linking fluoride exposure to neurodevelopmental and cognitive effects in humans. METHOD:A systematic review protocol was developed and utilized following the standardized OHAT systematic review approach for conducting literature-based health assessments. This monograph presents the current state of evidence associating fluoride exposure with cognitive or neurodevelopmental health effects and incorporated predefined assessments of study quality and confidence levels. Benefits of fluoride with respect to oral health are not addressed in this monograph. RESULTS:The bodies of experimental animal studies and human mechanistic evidence do not provide clarity on the association between fluoride exposure and cognitive or neurodevelopmental human health effects. Human mechanistic studies were too heterogenous and limited in number to make any determination on biological plausibility. This systematic review identified studies that assessed the association between estimated fluoride exposure and cognitive or neurodevelopmental effects in both adults and children, which were evaluated separately. The most common exposure assessment measures were drinking water concentrations and estimates of total fluoride exposure, as reflected in biomarkers such as urinary fluoride. In adults, only two high-quality cross-sectional studies examining cognitive effects were available. The literature in children was more extensive and was separated into studies assessing intelligence quotient (IQ) and studies assessing other cognitive or neurodevelopmental outcomes. Eight of nine high-quality studies examining other cognitive or neurodevelopmental outcomes reported associations with estimated fluoride exposure. Seventy-two studies assessed the association between fluoride exposure and IQ in children. Nineteen of those studies were considered to be high quality; of these, 18 reported an inverse association between estimated fluoride exposure and IQ in children. The 18 studies, which include 3 prospective cohort studies and 15 cross-sectional studies, were conducted in 5 different countries. Forty-six of the 53 low-quality studies in children also found evidence of an inverse association between estimated fluoride exposure and IQ in children. DISCUSSION:Existing animal studies provide little insight into the question of whether fluoride exposure affects IQ. In addition, studies that evaluated fluoride exposure and mechanistic data in humans were too heterogenous and limited in number to make any determination on biological plausibility. The body of evidence from studies in adults is also limited and provides low confidence that fluoride exposure is associated with adverse effects on adult cognition. There is, however, a large body of evidence on associations between fluoride exposure and IQ in children. There is also some evidence that fluoride exposure is associated with other neurodevelopmental and cognitive effects in children; although, because of the heterogeneity of the outcomes, there is low confidence in the literature for these other effects. This review finds, with moderate confidence, that higher estimated fluoride exposures (e.g., as in approximations of exposure such as drinking water fluoride concentrations that exceed the World Health Organization Guidelines for Drinking-water Quality of 1.5 mg/L of fluoride) are consistently associated with lower IQ in children. More studies are needed to fully understand the potential for lower fluoride exposure to affect children's IQ.
INTRODUCTION:Traffic-related air pollution (TRAP) contributes significantly to ambient air pollution, especially in urban settings. Air pollution has been established as a risk factor for hypertension and cardiovascular disease in adults, but this effect is less studied in other susceptible populations. There is increasing evidence that air pollution may adversely affect hypertensive disorders of pregnancy (e.g., gestational hypertension, preeclampsia, eclampsia). OBJECTIVE:Because reports indicate that air pollution may be linked to hypertensive disorders, the National Toxicology Program (NTP) conducted a systematic review to evaluate whether exposure to TRAP during pregnancy is associated with hypertensive disorders of pregnancy. METHODS:A systematic review protocol was developed and utilized for this evaluation that followed the Office of Health Assessment and Translation approach for conducting literature-based health assessments. This evaluation considered a range of traffic-related air pollutant measurements (e.g., fine particulate matter [PM2.5]) and traffic measures (e.g., proximity to major roads) in the literature search. Confidence ratings and level-of-evidence conclusions were developed for bodies of evidence for a given exposure measure when there was sufficient evidence (i.e., more than three studies). Changes in blood pressure during pregnancy, gestational hypertension, preeclampsia, eclampsia, or hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) syndrome were considered as measures of hypertension. Hazard conclusions were developed using a two-step process. First, confidence ratings were developed for individual air pollutants (e.g., PM2.5, nitrogen oxides [NOx]) and traffic measures (traffic density and proximity to major roads). Overall hazard conclusions were then developed for TRAP, considering the combined bodies of evidence across different individual measures of traffic-related pollutants. RESULTS AND EVIDENCE SYNTHESIS:The literature search and screening process identified 18 relevant epidemiological studies and one relevant animal study (from 344 potentially relevant references) that met the objective and the inclusion criteria. The human bodies of evidence for traffic-related PM2.5 and NO2 present a consistent pattern of findings that exposure to these pollutants is associated with the development of hypertensive disorders of pregnancy. There is a similar pattern of findings, but a smaller effect size, for bodies of evidence that residing in high-traffic density regions or in close proximity to major roads are associated with developing hypertensive disorders during pregnancy. There is a moderate level of evidence in the combined human body of evidence based primarily on the TRAP air pollutant studies with support from the traffic measures studies. There is an inadequate level of evidence in the animal body of evidence due to the lack of experimental animal studies identified for these measures. Evidence for other traffic-related pollutants that were identified (i.e., carbon monoxide [CO], black carbon [BC], and elemental carbon [EC]), including one animal study for CO, were few in number or provided inconsistent results across studies, and level-of-evidence conclusions were not reached. DISCUSSION AND CONCLUSION:NTP concludes that exposure to TRAP is presumed to be a hazard to pregnant women for developing hypertensive disorders of pregnancy. This conclusion was based on moderate confidence and moderate level of evidence in the combined body of evidence from human studies reporting on multiple measures of TRAP exposure (traffic-related PM2.5 and NO2) with support from studies on traffic measures (residing in high-traffic density regions or in close proximity to major roads during pregnancy). (This section of the abstract has been abridged.).
INTRODUCTION:Many cancer chemotherapy agents are known carcinogens, genetic toxicants, and developmental toxicants. Secondary malignancies, such as therapy-related acute myeloid leukemia, are caused by cancer chemotherapy agents administered to patients for the treatment of cancer. Occupational exposure to these agents was first documented in the 1970s and continues to occur, despite the issuance of safe handling guidelines in 1980s. OBJECTIVES:Based on the evidence of carcinogenicity and genetic toxicity associated with direct administration of cancer chemotherapy agents and current evidence of occupational exposure, the National Toxicology Program (NTP) conducted a systematic review to: (1) evaluate whether occupational exposure (e.g., medical, manufacturing, research, and veterinary) is associated with any adverse health outcomes in humans, and (2) summarize the prevalence and levels of chemotherapy agents in the workplace as measured by environmental monitoring and biomonitoring for possible worker exposures. METHODS:The evaluation was conducted following the Office of Health Assessment and Translation (OHAT) method. A literature search was performed up to February 23, 2017, using PubMed, Embase, Scopus, Toxline, and Web of Science. Relevant human studies were data extracted and assessed for risk of bias. Bodies of evidence were assessed to develop confidence ratings and level-of-evidence conclusions that reflect the certainty in the evidence that occupational exposure to cancer chemotherapy agents are associated with health effects on a per outcome basis. RESULTS AND EVIDENCE SYNTHESIS:The literature search and screening process identified 110 epidemiological studies relevant to assessing possible adverse health outcomes. Most studies addressing health outcomes evaluated potential DNA damage (n = 66; specifically, structural chromosomal aberrations (CA) and micronucleus (MN) induction and comet assay endpoints) and spontaneous abortion (n = 16). In addition to DNA damage, groups of studies were identified to evaluate the potential association between occupational exposure to cancer chemotherapy agents and adverse health outcomes, including cancer (three studies) and adverse effects on reproduction (30 studies). Additional health outcomes included acute effects, immune effects, and liver and kidney toxicity. One hundred seventy-one studies were identified to assess workplace exposure based on reporting of environmental contamination (107 studies) and urine and/or blood monitoring of these agents (82 studies). DISCUSSION AND CONCLUSIONS:NTP concluded that there is a moderate level of evidence that occupational exposure to chemotherapy agents is associated with increased incidence of spontaneous abortion, particularly when evaluating studies of nursing and pharmacy personnel. NTP also concluded that there is a moderate level of evidence that exposure to chemotherapy agents in the workplace is associated with genetic toxicity in humans based on consistent reports significantly higher levels of structural CA (% of cells with CA and number of CA), MN induction (number of cells with MN and number of MN) and DNA damage measured by comet assay (% tail DNA, tail length, tail moment, and DNA damage index) in exposed personnel. There was inadequate evidence for NTP to reach level-of-evidence conclusions on the remaining health outcomes, including cancer, primarily due to few studies per outcome and heterogeneity in the data. Despite current safety guidelines, cancer chemotherapy agents were commonly detected in environmental samples of the workplace (e.g., surface wipes and air sampling) and biosamples (e.g., urine or blood) of workers handling these agents, including data collected as recently as 2014 to 2016. Considering the potential for occupational exposure to these agents and the association between exposure and DNA damage and spontaneous abortions, there is a continued need to reduce exposures through training in safe handling procedures and provision and use of personal protective equipment and associated safety containment equipment. Health surveillance of occupationally exposed personnel would also benefit from improved exposure characterization methods, such as use of daily diaries that are assessed and validated to estimate exposure levels and additional environmental monitoring and biomonitoring data that include analytical chemistry approaches to assess multiple agents. There is also a need to better understand the sources (i.e., activities or physical locations) of worker exposure, especially in settings that have not been adequately studied (e.g., home care, veterinary clinics).
INTRODUCTION:Sarin (CASRN: 107-44-8) is a highly toxic organophosphorus nerve agent that was developed for chemical warfare during World War II and continues to be used in conflicts. Immediate effects of sarin exposure are well known, and although there are suggestions in the literature of neurological effects persisting after the initial signs have subsided, long-term neurological effects of acute exposure to sarin are not well characterized in humans. OBJECTIVE:The National Toxicology Program (NTP), on behalf of the National Institutes of Health (NIH) Countermeasures Against Chemical Threats program, conducted a systematic review to evaluate the evidence for long-term neurological effects in humans and nonhuman animals following acute exposure to sarin. (The terms "animal" and "animals" refer to nonhuman animals.). METHODS:A systematic review protocol was developed and utilized for this evaluation that followed the Office of Health Assessment and Translation approach for conducting literature-based health assessments. Any effect observed 24 hours after exposure (including days to years after exposure) was considered long term for this assessment. Because effects might vary based on time after exposure, the development of hazard conclusions was considered for three different time periods: initial (>24 hours-7 days after exposure), intermediate (8-364 days after exposure), and extended (greater than or equal to 1 year after exposure) periods. RESULTS AND EVIDENCE SYNTHESIS:The literature search and screening process identified 32 data sets within the 34 human studies and 47 data sets within the 51 animal studies (from 6,837 potentially relevant references) that met the objective and the inclusion criteria. Four main health effect categories of neurological response were identified as having sufficient data to reach hazard conclusions: (1) cholinesterase levels; (2) visual and ocular effects; (3) effects on learning, memory, and intelligence; and (4) morphology and histopathology in nervous system tissues. (This section of the abstract has been abridged.). DISCUSSION AND CONCLUSIONS:Hazard conclusions were considered for the four main health effect categories at all three time periods after exposure. The conclusions with the highest level of evidence for each time period were used to reach the overall conclusions. NTP concludes that acute sarin exposure is known to be a neurological hazard to humans in the initial time period of >24 hours-7 days after exposure based on suppression of cholinesterase. NTP concludes that acute sarin exposure is suspected to be a neurological hazard to humans in the intermediate time period of 8 days-1 year after exposure based on multiple effects, including suppression of cholinesterase, visual and ocular effects, and morphological and histological changes in nervous system tissues. NTP concludes that acute sarin exposure is suspected to be a neurological hazard to humans in the extended time period of greater than or equal to 1 year after exposure based on multiple effects, including effects on learning and memory and morphological and histopathological changes in nervous system tissues. DATA GAPS:This evaluation identified data gaps that contribute to lower confidence in the bodies of evidence for some endpoints and time periods after exposure. Future targeted research to assess the long-term neurological effects of sarin exposure should address areas with low confidence in the findings. Future research would benefit from the use of well-characterized human exposure data, use of exposed and appropriately matched control populations for neurological tests, and animal models that address the inconsistencies identified in this review using study design, conduct, and reporting practices to minimize bias. Given the hazard conclusions from this review, additional research on the four main health effect categories above may impact the confidence in the conclusions. Research may also be informative on a diverse range of neurological endpoints, identified in this report's appendices, for which there is inadequate evidence to determine whether there is an association with acute sarin exposure. Another area of research that the available data do not address is the effects of sarin on developing and aging brains. The current data are insufficient to assess if there are any susceptible populations.
