Abstract
Pyrethroids are commonly used around the home and in agricultural production to control insects. Human contact to one or more pyrethroid insecticides is likely. Numerous epidemiology studies have evaluated the association between health outcomes in humans and pyrethroid exposure. The purpose of this review was to identify and evaluate the quality of pyrethroid-related epidemiology studies that addressed chronic health effects, and compare findings with animal toxicology studies. We evaluated the quality of 61 studies published between 2000 and 2016 by using elements of outcome, exposure metric, exposure level, and study design. None of the 61 publications demonstrated strong quality for all elements. A few of the outcome measures were strong, particularly those relying upon medical diagnoses. Most of the pyrethroid epidemiology studies used a poor exposure metric, relying upon a single sample of pyrethroid urinary metabolites, which is subject to misclassification of past exposures. In addition, many studies were a cross-sectional design, preventing an evaluation of the temporality of the exposure-disease association. Furthermore, none of the effects observed in the epidemiological literature was concordant with toxicological effects noted in extensive testing of pyrethroids in animals. In order to provide more robust data on potential health outcomes from low dose exposure to pyrethroid insecticides, future epidemiological studies should fully characterize an adverse outcome, include exposure validation components, and quantify exposure over time.
Introduction
Pyrethroid insecticides belong to a class of chemistry that was derived from pyrethrins, which are found in chrysanthemum flowers as natural insecticides. Pyrethrins are esters of cyclopropane carboxylic acid and a cyclopentenolone alcohol that were synthetically modified to increase insecticidal potency and extend longevity in the presence of water, moisture, and sunlight (Elliott Citation1995). The chemical structures of pyrethroids are similar across the class and retain the essential acid/alcohol composition of pyrethrins. As a result, consideration of health effects can be made on the full class of pyrethroids (USEPA Citation2013a).
Depending on the region of the world, there are over a dozen registered pyrethroid molecules that are used in a myriad of products for agriculture, homeowner, veterinary, and medical applications. Specific pyrethroids include allethrin, bioallethrin, bifenthrin, cyfluthrin, cypermethrin, deltamethrin, d-phenothrin, esfenvalerate, fenvalerate, fenpropathrin, flumethrin, fluvalinate-tau, lambdacyhalothrin, permethrin, prallethrin, resmethrin, tefluthrin, and tetramethrin.
The use of pyrethroids has increased over the past two decades and correspondingly the opportunity for human exposure in the environment, home and diet. Absorbed pyrethroids are quickly metabolized and eliminated from the body. Although each pyrethroid has a unique kinetic profile, the plasma half-life of pyrethroids in general is less than 8 h (Kim et al. Citation2008; Godin et al. Citation2010; USEPA Citation2013a). Urinary metabolites of pyrethroid insecticides have been reported in population sampling programs (Health Canada Citation2013; Dewailly et al. Citation2014; Lewis et al. Citation2014; CDC Citation2015). While detection alone does not indicate that an adverse health outcome will occur, there is an ongoing interest in the potential associations of pyrethroid exposure and health effects, particularly at environmentally relevant levels.
Two reviews of epidemiology studies have presented a range of health outcomes associated with pyrethroid exposure (Koureas et al. Citation2012; Saillenfait et al. Citation2015). However, the authors provided little interpretation and no quality assessment of the reviewed studies.
The purpose of the current review was to conduct a comprehensive literature search, evaluate the study quality of the pyrethroid epidemiology publications, and discuss the concordance of effects reported in the epidemiological publications within the context of toxicology data. The objective was to identify studies for which exposure preceded the outcome, and both exposure and outcome had been determined with high-quality methods.
Methods
Identification of relevant studies
We used PubMed to search for epidemiology publications that evaluated human health outcomes and pyrethroid exposure from 2000 through 15 February 2016. Although discovered in the 1970s, pyrethroids were extensively commercialized in the 1990s, and relevant human health studies were conducted and published starting in 2000. Terms used in the search and additional details can be found in the Supplementary Material to this review.
The focus of this evaluation was to identify papers addressing chronic effects of pyrethroids in human populations. Epidemiology studies with estimated exposure to a specific pyrethroid or the class of pyrethroids were included. Excluded were review papers and commentaries on existing data. Also excluded were studies for which exposure was limited to “pesticides” or “insecticides” or “rural versus urban”. Cases of poisonings (and acute effects) were not reviewed because the acute effects of pyrethroids, including paresthesia and irritation are well known, and these reports tend to be case series without a control group. This process identified 82 potentially relevant publications. Initial review led to grouping the publications into five general outcome categories (male hormonal and reproductive effects; adverse outcomes at birth and in childhood; respiratory symptoms; immune system; and cancer and genotoxicity). Of the 82 publications, 21 addressed acute outcomes, general self-reported health effects, and other miscellaneous outcomes. These were not reviewed further. Search terms, flow chart, and studies not included are provided in the Supplementary Material. Sixty-one studies were included in the quality review process.
Quality assessment criteria
There are multiple approaches to report and evaluate study quality and validity (Sanderson et al. Citation2007; Rhomberg et al. Citation2013). Emphasis has been placed upon including quality assessments into the systematic review process (Adami et al. Citation2011; Muñoz-Quezada et al. Citation2013; Acquavella et al. Citation2016), particularly for regulatory purposes as proposed by the USEPA, Australian Pesticides and Veterinary Medicines Authority and the European Food Safety Authority, for example. In choosing to address study quality, we purposely did not tabulate risk estimates or report statistical testing to avoid the tendency to focus on selected positive (or negative) associations. While these components are informative for causal inference and encompass much of the discussions about human health risk, we strove to limit this stage of the evaluation to an assessment only of quality and concordance.
The current review followed the general approach of Adami et al. (Citation2011), which is to parse the relevant publications with a quality assessment, excluding studies with severe limitations from a weight-of-evidence evaluation. Whereas Adami et al. (Citation2011) do not provide a quality evaluation process, Muñoz-Quezada et al. (Citation2013) proposed a scoring system for select study parameters. However, the summary score can classify large studies with sophisticated analytical methods as “high” quality but overshadow a critical weakness, such as in exposure assessment, which ultimately could bias the results. Lakind et al. (Citation2014) proposed ranking individual study characteristics in their Biomonitoring, Environmental Epidemiology, and Short-lived Chemicals (BEES-C) instrument rather than an overall score, using colors to visually aid evaluating a group of studies. The BEES-C was recently recommended in the National Toxicology Program Office of Health Assessment and Translation (OHAT) approach for systematic review (NTP Citation2015).
We used a modified approach based on the parameters suggested by Muñoz-Quezada et al. (Citation2013) and used the three primary elements of outcome, exposure metric, and study design to evaluate quality. These elements were consistent with the primary review objective. Additional quality parameters may be considered later for a causal assessment and application of studies for human health risk assessment.
Since many of the studies relied upon biomonitoring, we also included the mean concentration of a commonly reported urinary metabolite, 3-phenoxybenzoic acid (3-PBA), in the quality assessment. Thus, if the study metric indicated the measurement of 3-PBA, we considered the concentration as an additional indicator of quality. Therefore, for some studies, we used four elements for quality assessment.
shows the four elements and the criteria for each element that led to a rank of “strong,” “neutral,” or “poor.” An element that was “strong” was shaded green and the cell of a “poor” element was shaded red. “Neutral” elements were left unshaded.
Table 1. Definition of ratings for study quality.
The outcome element encompasses the validity of the disease or health outcome. Outcomes that were based upon evaluations by a medical provider (e.g. birth weight), or a medical diagnosis (autism or cancer) were considered to be strong. Diseases and symptoms that were self-reported as well as scores based upon screening tests, interviews, and checklists were considered “neutral”, and not ranked poor or strong. Standard test batteries were also assigned as neutral since the outcomes can be influenced by the testing environment, examiner, and age of the subjects at the time of examination, for example (Li et al. Citation2012). The outcomes based upon the measurement of a short-lived hormone were considered to be poor if only one sample was collected because these measurements are highly variable with time and circumstances and require multiple samples to establish status. Characteristics of sperm or semen based on a single sample were similarly considered poor.
The exposure metric ranged from documented occupational data (strong), self-reported occupational use (application or manufacture) (neutral), to single samples of a pyrethroid in urine or blood (poor). Since pyrethroids are quickly metabolized and cleared from the body within the day of ingestion, spot samples (i.e. one sample taken at one “spot” in time) are influenced by the timing relative to exposure (Hays et al. Citation2008). Single samples are susceptible to inter- and intra-individual variability and may misclassify past exposure (Hays et al. Citation2009; Aylward et al. Citation2014; Morgan et al. Citation2016a). Sources of pyrethroid exposure that are known to be continuous or at a steady state may provide more reliable biomonitoring estimates, even from a single sample. An example would be if an important dietary element were consumed daily, such as from coffee (Morgan et al. Citation2016b). Similarly, when urine collection is timed with a known application, the urinary concentration can be used to inform other exposure tools, such as from questionnaires (Hines et al. Citation2008; Thomas et al. Citation2010a). However, the degree of error and risk of bias should be identified in these studies (Lakind et al. Citation2014). Ecological estimates based upon proximity to an application were also classified as poor. While the potential for exposure exists, it does not necessarily mean that marked exposure had occurred. Efforts to validate assumption of bystander exposure have indicated that personal behaviors, rather than being near an application, are determinants of individual exposure (Alexander et al. Citation2006; Galea et al. Citation2015).
The exposure level parameter was intended to highlight studies in which the participants had a 3-PBA urinary concentration higher than background as identified in the US population biomonitoring programs (CDC Citation2015). Up to 18 pyrethroids are metabolized in the body and the environment to 3-PBA (Barr et al. Citation2010). In the US from 1999 to 2010, the 50th percentile range of urinary 3-PBA was 0.25–0.40 µg/l; the 75th percentile range was 0.50–1.06 µg/l. Globally, these ranges are similarly observed in most non-occupational settings (Saillenfait et al. Citation2015). For this review, studies with a mean 3-PBA level at or below 1 µg/l were considered to be low quality. At low levels, the detection of 3-PBA may reflect primary exposure to 3-PBA or substances that result in the presence of 3-PBA in urine rather than exposure to a pyrethroid insecticide.
Cohort and case control study designs were both considered to be strong. The limitation to case control studies is often due to biased recall of exposure, which was evaluated separately in this review. Cross-sectional studies were considered to be poor quality. Given the toxicokinetic properties of pyrethroid insecticides, (e.g. short half-life in the body), this design when combined with spot samples has limited reliability and validity as demonstrated by the analysis of the cross-sectional data of the US National Health and Nutrition Examination Survey (NHANES) (Lakind et al. Citation2012).
Toxicology
Toxicity testing in animals is conducted to provide a plausible description of potential adverse effects that could occur in humans and the dose levels at which they could occur. Therefore, a reasonable assumption is that adverse effects in toxicology studies will correspond with adverse outcomes asserted in epidemiology studies, particularly at the highest exposures to humans, bearing in mind that there may not be a perfect correspondence of toxicology studies with epidemiology findings. Toxicological effects that are noted across a broad array of dose levels in several species is a starting point in describing plausible outcomes in human populations. Based on that logic, we compared the epidemiology outcomes to toxicology findings as a test for concordance.
Pyrethroids have ample evidence in animal studies that can be used to identify plausible effects in humans. According to guidelines set forth in the US Code of Federal Regulations, Title 40, Chapter I, Subchapter E, Part 158.500, each pyrethroid must be tested in animals for potential effects in every organ and organ system and for life stage effects (reproductive and developmental endpoints). The extensive test guideline and literature data have contributed to understanding what pyrethroids can do in biological systems and supported the USEPA’s collection of pyrethroids into a common mechanism group, which led to a cumulative assessment of risk.
Evidence for toxicological effects in animal studies was taken from four sources: the USEPA’s cumulative risk assessment of the pyrethroids (USEPA Citation2013a), responses to the pyrethroid cumulative assessment (USEPA Citation2013b), a review of pyrethroid toxicity by Soderlund et al. (Citation2002), and assessments of individual pyrethroids by the Joint FAO/WHO Meeting on Pesticide Residues (WHO Citation2017). These four authoritative sources provide a peer-reviewed, international, and inter-regulatory consensus on pyrethroid-related effects and corresponding dose levels.
Results
Quality of epidemiology studies
Male hormonal and reproductive effects
The collective evidence for male hormonal and reproductive effects was methodologically very weak. There were 15 publications (13 studies) that addressed sperm quality and/or a disruption in sperm genetic integrity (). Most relied upon a single semen sample (n = 10), a spot urine sample (n = 9) that was within the range of the general population (n = 6) and all were a cross sectional design. The exposure metric was considered strong for three investigations that were among the few occupational settings. These focused on a single pyrethroid and evaluated air and dermal samples to confirm fenvalerate exposure to a group of factory workers in China (Bian et al. Citation2004; Xia et al. Citation2004; Lifeng et al. Citation2006).
Table 2. Male hormonal and reproductive effects.
All five identified studies of male hormone levels () were cross-sectional studies, for which four used single samples of plasma hormones. Only one of the four urinary pyrethroid metabolites samples was above 1 µg/l (Han et al. Citation2008). The occupational study that evaluated sprayers in two seasons was not specific to pyrethroids (Kamijima et al. Citation2004).
Two studies with mixed quality addressed fertility (). Sallmen et al. (Citation2003) evaluated pyrethroid exposure in male greenhouse workers. As an occupational study, exposure was likely higher and more frequent than population-based studies. However, detailed analyzes by specific pesticides were not conducted. Whitworth et al. (Citation2015) focused on decreased fertility as measured by serum levels of the anti-Mullerian hormone in women. While actual exposure to pyrethroid was not measured, the study population was likely exposed from insect control for malaria in the home.
Adverse outcomes at birth and in childhood
The 11 publications (8 studies) that evaluated birth weight and other infant health characteristics were characterized by strong outcome measures, but many relied upon a poor exposure metric (n = 5) ().
Table 3. Adverse outcomes at birth and in childhood.
Only three publications (2 studies) addressed birth defects and pyrethroid exposure (). Both studies used ecological records of pesticide application and maternal residence to poorly infer exposure.
Four studies evaluated in utero exposure and childhood development at various ages and with different tests (). All relied upon a poor estimate of in utero exposure but were marked by strong study design. None controlled for exposure in the growing child.
The eight studies of developmental delay and autism spectrum disorder with childhood exposure () were collectively of limited quality. Most relied upon a self-reported test or battery (n = 7), evaluated exposure using a spot sample or ecological indicator (n = 7) with background population levels (n = 5) and a cross sectional design (n = 6).
Respiratory outcomes
The two publications on respiratory outcomes related to prenatal exposure were both from the Columbia Center for Children’s Environmental Health (CCCEH) (Reardon et al. Citation2009; Liu et al. Citation2012) (). These publications relied upon self-reported outcomes, the use of spot samples, and while a prospective cohort of growing children, the investigators also conducted cross sectional analyzes of exposure at age 5–6 years.
Table 4. Respiratory outcomes.
With respect to adult exposure and respiratory symptoms (), the Agricultural Health Study (AHS) dominates this literature with 10 of the 13 publications. While the AHS is a large prospective study of more than 80,000 private and commercial applicators and their spouses, the analyzes of self-reported respiratory effects were all cross sectional. The strength of the AHS occupational exposure is tempered in that all pesticide information is self-reported.
The other three publications on respiratory outcomes were characterized by poor exposure metrics that were based on spot sampling or residence near an application (Karpati et al. Citation2004; Mwanga et al. Citation2016; Quansah et al. Citation2016).
Effects on the immune system
Two of the four epidemiology studies with a focus on the immune system () evaluated pesticide groups and were not specific to pyrethroid exposure (Costa et al. Citation2013, Citation2014). The other studies (three publications) were weakly characterized by spot urine samples and cross-sectional design (Neta et al. Citation2010, Citation2011; Mwanga et al. Citation2016).
Table 5. Adult exposure leads to effects on the immune system.
Cancer and genotoxicity
All three publications of cancer in adults were from the AHS (). The cancer diagnoses were confirmed from the state-wide registries but the exposure assessment from self-reported use has limitations.
Table 6. Cancer and genotoxicity.
The three studies of cancer in children () also had strong outcome quality but were characterized by poor exposure assessment (Ding et al. Citation2012; Ferreira et al. Citation2013; Malagoli et al. Citation2016).
Three of the four studies of genotoxicity were not specific to pyrethroid use (Ogut et al. Citation2011; Kasiotis et al. Citation2012; Costa et al. Citation2014) ().
Pyrethroid-related toxicological effects and plausibility analysis
The most sensitive toxicological endpoints from acute, sub-chronic, or chronic exposure in animal studies are neurological symptoms (Clark Citation1995; Soderlund et al. Citation2002). Type I symptoms are aggressive sparring, increased sensitivity to external stimuli, and fine tremors, progressing to whole body tremors. Type II symptoms include pawing and burrowing, profuse salivation, and course tremors, progressing to seizures. Some pyrethroids induce mixed Type I and II neurological symptoms. The mode of action is via voltage-gated sodium channel alterations that results in altered neuronal excitability without pathological damage to neuronal structures. No other effects have been noted without concomitant neurological effects (Clark Citation1995; Soderlund et al. Citation2002).
No other toxicities are considered to be more potent or pertinent than neurological symptoms (USEPA Citation2013a). The USEPA grouped pyrethroids into a common mechanism group for assessment of cumulative risk based on the interaction with sodium channels, a key event in the neurotoxicity of pyrethroids. Furthermore, as part of the USEPA’s process for cumulative risk review, they responded to stakeholder concerns for adverse effects (USEPA Citation2013c). In their responses, the USEPA addressed questions about adverse effects that are relevant to the categories of outcomes for the pyrethroid epidemiology studies in this review. A clear understanding of plausible pyrethroid-related adverse effects in humans can be based on USEPA’s cumulative review of the pyrethroids and the individual pyrethroid toxicological monographs that were prepared by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) (WHO Citation2017).
For male hormonal and reproductive effects cited in epidemiology studies, the toxicological correlate is endocrine effects. For adverse outcomes at birth and in childhood, the corresponding studies would be developmental toxicity in animals. Respiratory outcomes reported in epidemiology studies would be analogous to inhalation studies in toxicology studies. The final two categories, immune system effects and cancer are specifically tested in animals.
Endocrine effects/sperm effects/hormonal levels/decreased fertility
Each of the pyrethroids was tested for potential effects on the estrogen, androgen, and thyroid pathways via whole animal reproduction and developmental neurotoxicity studies. EPA concluded after reviewing 29 toxicology studies that included 18 pyrethroids, “…effects on pubertal development is not the critical toxicity.” The “critical toxicity” is neurological effects, for which no-effect levels have been established (USEPA Citation2013c).
The USEPA’s Endocrine Disruptor Screening Program (EDSP) examined four pyrethroids (cypermethrin, cyfluthrin, esfenvalerate, and permethrin) for evidence of effects on the endocrine, androgen, or thyroid hormone pathways (USEPA Citation2015a, Citation2015b, Citation2015c, Citation2015d). No endocrine-related effects were noted, with the exception of very weak literature-based evidence for cypermethrin- and permethrin-related effects on the androgen pathway (Hu et al. Citation2013; Li et al. Citation2013). This evidence is considered to be very weak because no androgenic or anti-androgenic effects on reproductive parameters were reported in regulatory-compliant mammalian studies and there is no evidence of interaction with the androgen pathway in the EDSP Tier 1 assays.
Plausibility analysis: Pyrethroids are highly unlikely to affect human estrogen, androgen, or thyroid hormonal pathways and adversely affect human fertility or reproductive capability.
Developmental neurotoxicity and childhood sensitivity
The USEPA evaluated effects on the developing fetus and childhood sensitivity by reviewing over 70 guideline toxicity studies for 24 pyrethroids submitted to the Agency and concluded that pyrethroids do not directly impact developing fetuses or post-natal development (USEPA Citation2006, Citation2011, Citation2013b, p. 3).
Plausibility analysis: Developmental and reproduction studies in animals indicate that pyrethroids would not have an adverse effect on birth outcome and infant health at birth.
Although standard animal protocols are not optimized to detect specific diagnoses such as autism and intelligence delay, related behavioral changes would nevertheless have been noted in the broad range of dose levels administered to animals, including the large, maximally tolerated doses. Animal studies with pyrethroids found no changes in behavior related to developmental delay or symptomology that could be associated with autism spectrum disorder.
Respiratory outcomes (Asthma/Wheeze)
The USEPA reviewed the relationship between pyrethrins/pyrethroid exposure and allergies/asthma, and concluded that the available animal experimental data did not show a relationship between exposure to products containing pyrethrins or pyrethroids and allergic or asthma responses (USEPA Citation2013c). As a consequence of that conclusion, the Agency does not require additional warnings or label statements specific to asthmatics on pyrethroids and pyrethrins end-use product labels.
Plausibility analysis: Pyrethroids are unlikely to induce allergic or asthma responses. However, the parasthetic effects of pyrethroids on sensory nerve fibers may lead to episodic coughing from inhalation of sprays.
Immunotoxicity
The USEPA concluded that there was no consistent evidence from guideline studies for adverse effects on the immune system in mice, rats, or dogs for any of the pyrethroid pesticides (USEPA Citation2013b) and recommended that no further immunotoxicity studies were required.
Plausibility analysis: Pyrethroids are unlikely to have any effect on the human immune system, particularly at doses lower than observable neurotoxicity.
Cancer
Each of the pyrethroids was tested in regulatory-compliant long-term carcinogenicity assays and classified with regard to carcinogenic potential. Of the pyrethroids listed in the USEPA’s 2015 Annual Cancer Report (USEPA Citation2015e), three were classified as “possible” (alpha-cypermethrin, cypermethrin, and bifenthrin) human carcinogens and permethrin was classified as a “likely” human carcinogen. Permethrin’s classification was based on two reproducible benign tumor types (lung and liver) in the mouse that were observed in lifetime studies at the extremely high daily dietary dose levels of 2500 and 5000 mg permethrin/kg diet. The Joint FAO/WHO Meeting on Pesticide Residues on permethrin stated that “the weight of evidence supports the conclusion that permethrin has very weak oncogenic potential and the probability that it has oncogenic potential in humans is remote” (WHO Citation1999). The remaining pyrethroids were classified as “not likely”, “not classifiable”, or having “evidence of non-carcinogenicity.”
Plausibility analysis: Toxicological testing on pyrethroids indicates a weak, if any, effect on the incidence of tumors. For permethrin, cypermethrin, and bifenthrin there is evidence for an increased incidence of liver and/or lung tumors. However, tumors were only detected at the highest doses tested, which is many orders of magnitude higher than any human exposure.
Summary of epidemiology endpoints and toxicological evidence
compares evidence in animal studies with the five general areas of reported findings and 13 outcome categories identified from the reviewed epidemiological studies. The toxicological evidence indicates that no effects are expected for male reproductive effects, birth outcomes, developmental outcomes in children, respiratory outcomes, and the immune system. The one exception is the general category of cancer. The toxicological studies showed weak effects in lung and liver. However, the epidemiology studies did not indicate that these organs were affected (Rusiecki et al. Citation2009; Koutros et al. Citation2010; Alavanja et al. Citation2014). Additional AHS publications observed no association of permethrin exposure and lung cancer (Alavanja et al. Citation2004; Bonner et al. Citation2017).
Table 7. Concordance of epidemiological and toxicological evidence.
Discussion
From more than 2000 peer-reviewed publications on pyrethroids, we conducted a quality review of 61 epidemiology studies that were specific to pyrethroid exposure. The degree of quality was based on a modification of several other quality evaluation techniques (Muñoz-Quezada et al. Citation2013; LaKind et al. Citation2014; Acquavella et al. Citation2016), and addressed four quality elements: outcome, exposure metric, urinary 3-PBA level, and study design. While others have reviewed the epidemiology and exposure literature, this is the first to apply quality tools.
The primary objective of the quality assessment was to first confirm that each publication could reliability determine both disease and exposure (to a particular pyrethroid or the class) and that exposure preceded disease. Other tools exist for evaluating strength of evidence (Moher et al. Citation2001; Vandenbroucke et al. Citation2007; Owens et al. Citation2010; Youngstrom et al. Citation2011); however, these have multiple elements, some of which are subjective. We also did not attempt to provide an overall score or rank to the studies. Instead, following the suggestion of the BEES-C instrument, we color coded the tabular cells for each quality element (LaKind et al. Citation2014).
We looked at the overall quality across all studies. First, even with only four elements, no single study exhibited strong characteristics for all parameters. Second, only a few studies were mixed with strong and neutral quality (i.e. had no poor-quality elements). There were two studies of infant health that evaluated exposure early in pregnancy (strong design) and relied upon a medical diagnosis (strong outcome) (Kennedy et al. Citation2005; Mytton et al. Citation2007). Neither reported a statistically significant adverse association of exposure and birth outcome. The cancer publications of the AHS were also characterized by a strong outcome and strong prospective design, relying upon a neutral quality exposure element of self-reported occupational use. The AHS observations for cancer identified an association of multiple myeloma with the highest exposure category of lifetime-exposure-days (Rusiecki et al. Citation2009; Alavanja et al. Citation2014). The scope of null findings is, of course, unknown. As in the example of the AHS and lung cancer, negative findings were not featured in the publications and, as a result, “pyrethroids” were not identified in the search terms (Alavanja et al. Citation2004; Bonner et al. Citation2017). This is a limitation of systematic reviews, in general, that negative observations cannot be captured because the authors do not highlight such findings in the publications.
Third, many of the studies had no strong element at all. Specifically, those of the male reproductive outcomes were characterized by poor outcome (single sample of sperm or hormone), poor exposure metric (spot urine sample), poor exposure level (3-PBA below population background), and poor design (cross-sectional).
Determining exposure retrospectively is a difficult task in epidemiology studies. Most of the pyrethroid epidemiology publications relied upon poor to neutral quality exposure estimates from single samples of urinary metabolites, proximity to an application, or self-reported use. Each presents an opportunity for improvement. For short lived chemicals, such as the pyrethroids, the urinary metabolites provide only a snapshot of recent exposures, typically within the previous 24 h. Given that pyrethroids are quickly metabolized, the presence or absence of pyrethroid metabolites in urine does not inform if the concentration represents a typical or atypical (i.e. peak) exposure. A recent study in the US of 50 study subjects identified consumption of coffee and bread to be associated with urinary 3-PBA levels (Morgan et al. Citation2016b). Additional studies that collect repeated samples and information about sources of exposure would provide better insight into recent and past exposure, and those sources that are routine versus episodic.
There were 10 studies for which the mean urinary 3-PBA level was above 1 µg/l. With higher urinary concentrations, the disease–exposure relationship may be more likely. The highest mean concentration, at 18.3 µg/l, was reported in the only US study of the 10 (Berkowitz et al. Citation2004). The authors found no significant difference for the four birth outcomes and 3-PBA after controlling for potential confounders. Spraying for West Nile Virus in New York City may explain the 3-PBA levels. The five studies from China reported significant associations with higher 3-PBA in urine and reduced sperm concentrations (Perry et al. Citation2007; Xia et al. Citation2008; Ji et al. Citation2011), increased luteinizing hormone levels (Han et al. Citation2008), and childhood developmental score (Xue et al. Citation2013). The other studies from Italy, Thailand and South Africa reported no association with autism spectrum disorder (Domingues et al. Citation2016), an association with cytokine but not asthma (Mwanga et al. Citation2016) or did not evaluate pyrethroid exposure (Costa et al. Citation2013; Fiedler et al. Citation2015). The validity of these findings is limited by the single sample for outcomes (semen, hormone), spot sample of urine, and cross-sectional design.
An ecological approach, using application records and geo-positioning was an exposure metric for several of the pyrethroid studies. Other investigators have sought to validate or quantify an internal dose (i.e. exposure) to nearby residents following an application, and the few data suggest that exposure from drift is minimal (Arbuckle et al. Citation2004; Curwin et al. Citation2005; Mandel et al. Citation2005; Galea et al. Citation2015). Opportunities to improve this assignment include collecting data on application equipment, formulation, and weather conditions (i.e. wind direction).
Exposure assessment from self-reported use based on questionnaires has clear limitations. The use of a specific pesticide could be inaccurately reported, and the internal dose may vary for each person. The AHS investigators have shown that respondents can recall use reliably (Blair et al. Citation2000). However, use alone does not lead to homogeneous internal dose in applicators as measured in urine samples (Hines et al. Citation2003, Citation2008; Thomas et al. Citation2010a, Citation2010b). As a result, the AHS can only create qualitative categories (based on lifetime days applied) and is poorly equipped to quantify the exposure resulting from the reported application(s). We recommend additional validation efforts among occupational groups with urine sampling that is timed with a pyrethroid application. Contemporaneous sampling would provide information that could be incorporated into questionnaires of past exposure.
In contrast, the exposures evaluated in the many animal studies utilized a wide span of distinct doses administered daily up to and including maximally tolerated doses. The outcomes under study suggest that no adverse effects at exposure levels reported in humans are expected. Neurological effects such as tongue and lip numbness, lethargy, muscle tremors, respiratory failure, vomiting, diarrhea, or seizures are the most sensitive and potent effect for the class of pyrethroids. Health-based guidance limits for exposure (e.g. acute, short- and long-term) of humans are based on known neurological effects that arise from a well-defined adverse outcome pathway. We noted no concordance in observed outcomes in the reviewed epidemiology studies with the toxicological profile for pyrethroids.
The many instruments that provide guidance in reporting and interpretation of epidemiology data demonstrate the need for quality epidemiology research. As the reliance upon animal toxicology data declines, the importance of valid and reliable epidemiology data increases. To be used for human health risk assessment, proposals for future environmental epidemiology studies should improve the status quo for evaluation of exposure to pyrethroids (and other pesticides) and confirming health effects. The barriers to study quality entail a balance of cost, time and burdens to the study subject (s). A broader conversation is needed to recognize the different purposes of human data, e.g. clinical, research and regulation (risk assessment). A case in point is collecting two semen samples in clinical settings to establish a diagnostic category, but one sample may be sufficient to develop research hypotheses (Chiu et al. Citation2017). To test hypotheses, particularly for human health risk assessment, minimizing the risk of bias is more important than statistical precision. Epidemiologists and those who rely on human data must begin to agree on best practices.
Conclusions
This comprehensive review of the pyrethroid epidemiology literature presents quality criteria to evaluate the body of the evidence. Furthermore, this review compares epidemiology outcomes to adverse effects in animal testing that have been well established for this class of chemistry. Considering the poor exposure quantification and weak study designs, the epidemiology publications neither confirm nor refute the broad and deep literature on effects of pyrethroids in laboratory animals. The collective epidemiology evidence is methodologically weak, with imprecise and/or unreliable exposure measurements. Based on longer-term toxicity studies, plausible outcomes in human populations that fall along the adverse outcome pathway would be primarily neurological symptoms, which were not a feature of any of the epidemiology studies. The conversation about setting quality guidelines for epidemiology is growing. Certainly, there are barriers to achieving an “ideal” epidemiology study. However, defining these quality components is important so that researchers and evaluators can work toward the same goal. This is particularly important as reliance upon animal studies is declining and epidemiology studies for risk assessment are increasing. In order to provide more robust data on the potential health outcomes from low-dose exposure such as to pyrethroid insecticides, future epidemiology studies should fully characterize an adverse outcome, include exposure validation components, and quantify exposure over time.
Declaration of interest
The author’s current employment affiliation is shown on the cover page. Dr. Burns was previously employed by The Dow Chemical Company, which does not manufacture pyrethroid insecticides. Dr. Pastoor was previously employed by Syngenta Crop Protection, a registrant of pyrethroid insecticides. Currently, each author (Drs Burns and Pastoor) has established an independent consulting practice. Neither Drs Burns nor Pastoor has been part of any pyrethroid regulatory submissions in the last 5 years. Furthermore, neither has appeared in any litigation regarding pyrethroids. This work was conducted with financial support from the Pyrethroid Working Group (PWG). The PWG is made up of companies owning the technical registrations on the active ingredients in pyrethroid insecticide products. The companies include Amvac, BASF, Bayer CropScience, FMC, Syngenta, and Valent BioSciences. The PWG was given the opportunity to offer comments on the draft manuscript. More information on the PWG is available at the following website: www.pyrethroids.com. The purpose of this review was to allow input on the clarity and completeness of the science presented but not in interpretation of the findings. The review, synthesis, and conclusions reported in this paper are the exclusive professional work product of the authors and do not necessarily represent the views of the PWG or the member companies.
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The authors thank Kathryn Shlee for conducting the extensive PubMed searches. We also gratefully acknowledge the very useful comments of three reviewers who were selected by the Editor and anonymous to the authors. Addressing those comments helped improve the paper and its readability.
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