A simulation study of extrapolation uncertainty in exposure assessment - Use of pilot study results for site investigation.

Accurate characterization of soil contaminant concentrations is often crucial for assessing risks to human and ecological health. However, fine-scale assessments of large tracts of land can be cost prohibitive due to the number of samples needed. One solution to this problem is to extrapolate sampling results from one area to another unsampled area. In the absence of a validated extrapolation methodology, regulatory agencies have employed policy-based techniques for large sites, but the likelihood of decision errors resulting from these extrapolations is largely unexplored. This study describes the results of a simulation study aimed at guiding environmental sampling for sites where extrapolation concepts are of interest. The objective of this study is to provide practical recommendations to regulatory agencies for extrapolating sampling results on large tracts of land while minimizing errors that are detrimental to human health. A variety of site investigation scenarios representative of environmental conditions and sampling schemes were tested using adaptive sampling when collecting discrete samples or applying incremental sampling methodology (ISM). These simulations address extrapolation uncertainty in cases where a Pilot Study might result in either false noncompliance or false compliance conclusions. A wide range of plausible scenarios were used that reflect the variety of heterogeneity seen at large sites. This simulation study demonstrates that ISM can be reliably applied in a Pilot Study for purposes of extrapolating the outcome to a large area site because it decreases the likelihood of false non-compliance errors while also providing reliable estimates of true compliance across unsampled areas. The results demonstrate how errors depend on the magnitude of the 95% upper confidence limit for the mean concentration (95UCL) relative to the applicable action level, and that error rates are highest when the 95UCL is within 10%-40% of the action level. The false compliance rate can be reduced to less than 5% when 30% or more of the site is characterized with ISM. False compliance error rates using ISM are insensitive to the fraction of the decision units (DUs) that are characterized with three replicates (with a minimum of 10 percent), so long as 95UCLs are calculated for the DUs with one replicate using the average coefficient of variation from the three replicate DUs.

Global patterns and correlates in the emergence of antimicrobial resistance in humans.

Antimicrobial resistance (AMR) is a critical global health threat, and drivers of the emergence of novel strains of antibiotic-resistant bacteria in humans are poorly understood at the global scale. We examined correlates of AMR emergence in humans using global data on the origins of novel strains of AMR bacteria from 2006 to 2017, human and livestock antibiotic use, country economic activity and reporting bias indicators. We found that AMR emergence is positively correlated with antibiotic consumption in humans. However, the relationship between AMR emergence and antibiotic consumption in livestock is modified by gross domestic product (GDP), with only higher GDP countries showing a slight positive association, a finding that differs from previous studies on the drivers of AMR prevalence. We also found that human travel may play a role in AMR emergence, likely driving the spread of novel AMR strains into countries where they are subsequently detected for the first time. Finally, we used our model to generate a country-level map of the global distribution of predicted AMR emergence risk, and compared these findings against reported AMR emergence to identify gaps in surveillance that can be used to direct prevention and intervention policies.

Human interactions with bats and bat coronaviruses in rural Côte d'Ivoire.

Bats are presumed reservoirs of diverse α- and ß- coronaviruses (CoVs) and understanding the diversity of bat-CoVs and the role bats play in CoV transmission is highly relevant in the context of the current COVID pandemic. We sampled bats in Côte d'Ivoire (2016-2018) living at ecotones between anthropogenic and wild habitats in the Marahoué National Park, a recently encroached protected area, to detect and characterize the CoVs circulating in bats and humans. A total of 314 bats were captured, mostly during the rainy season (78%), and CoV RNA was detected in three of the bats (0.96%). A CoV RNA sequence similar to Chaerephon bat coronavirus/Kenya/KY22/2006 (BtKY22) was found in a Chaerephon cf. pumilus and a Mops sp. fecal swab, while a CoV RNA sequence similar to the two almost identical Kenya bat coronaviruses BtKY55 and BtKY56 (BtKY55/56) was detected in an Epomops buettikoferi oral swab. Phylogenetic analyses indicated differences in the degree of evolutionary host-virus co-speciation for BtKY22 and BtKY55/56. To assess potential for human exposure to these viruses, we conducted human syndromic and community-based surveillance in clinics and high-risk communities. We collected data on participant characteristics, livelihoods, animal contact, and high-risk behaviors that may be associated with exposure to zoonotic diseases. We then collected biological samples for viral testing from 401 people. PCR testing of these biological samples revealed no evidence of CoV infection among the enrolled individuals. We identified higher levels of exposure to bats in people working in crop production and in hunting, trapping and fishing. Finally, we used the 'Spillover' risk-ranking tool to assess the potential for viral spillover and concluded that, while there is no evidence to suggest imminent risk of spillover for these CoVs, their host range and other traits suggest caution and vigilance are warranted in people with high exposure risk.

Behavioral-biological surveillance of emerging infectious diseases among a dynamic cohort in Thailand.

BACKGROUND: Interactions between humans and animals are the key elements of zoonotic spillover leading to zoonotic disease emergence. Research to understand the high-risk behaviors associated with disease transmission at the human-animal interface is limited, and few consider regional and local contexts. OBJECTIVE: This study employed an integrated behavioral-biological surveillance approach for the early detection of novel and known zoonotic viruses in potentially high-risk populations, in an effort to identify risk factors for spillover and to determine potential foci for risk-mitigation measures. METHOD: Participants were enrolled at two community-based sites (n = 472) in eastern and western Thailand and two hospital (clinical) sites (n = 206) in northeastern and central Thailand. A behavioral questionnaire was administered to understand participants' demographics, living conditions, health history, and animal-contact behaviors and attitudes. Biological specimens were tested for coronaviruses, filoviruses, flaviviruses, influenza viruses, and paramyxoviruses using pan (consensus) RNA Virus assays. RESULTS: Overall 61/678 (9%) of participants tested positive for the viral families screened which included influenza viruses (75%), paramyxoviruses (15%), human coronaviruses (3%), flaviviruses (3%), and enteroviruses (3%). The most salient predictors of reporting unusual symptoms (i.e., any illness or sickness that is not known or recognized in the community or diagnosed by medical providers) in the past year were having other household members who had unusual symptoms and being scratched or bitten by animals in the same year. Many participants reported raising and handling poultry (10.3% and 24.2%), swine (2%, 14.6%), and cattle (4.9%, 7.8%) and several participants also reported eating raw or undercooked meat of these animals (2.2%, 5.5%, 10.3% respectively). Twenty four participants (3.5%) reported handling bats or having bats in the house roof. Gender, age, and livelihood activities were shown to be significantly associated with participants' interactions with animals. Participants' knowledge of risks influenced their health-seeking behavior. CONCLUSION: The results suggest that there is a high level of interaction between humans, livestock, and wild animals in communities at sites we investigated in Thailand. This study highlights important differences among demographic and occupational risk factors as they relate to animal contact and zoonotic disease risk, which can be used by policymakers and local public health programs to build more effective surveillance strategies and behavior-focused interventions.

A global repository of novel antimicrobial emergence events.

Despite considerable global surveillance of antimicrobial resistance (AMR), data on the global emergence of new resistance genotypes in bacteria has not been systematically compiled. We conducted a study of English-language scientific literature (2006-2017) and ProMED-mail disease surveillance reports (1994-2017) to identify global events of novel AMR emergence (first clinical reports of unique drug-bacteria resistance combinations). We screened 24,966 abstracts and reports, ultimately identifying 1,757 novel AMR emergence events from 268 peer-reviewed studies and 26 disease surveillance reports (294 total). Events were reported in 66 countries, with most events in the United States (152), China (128), and India (127). The most common bacteria demonstrating new resistance were Klebsiella pneumoniae (344) and Escherichia coli (218). Resistance was most common against antibiotic drugs imipenem (89 events), ciprofloxacin (84) and ceftazidime (83). We provide an open-access database of emergence events with standardized fields for bacterial species, drugs, location, and date. We discuss the impact of reporting and surveillance bias on database coverage, and we suggest guidelines for data analysis. This database may be broadly useful for understanding rates and patterns of AMR evolution, identifying global drivers and correlates, and targeting surveillance and interventions.

Addendum to Iwai and Hoberman (2014)-Reassessment of Developmental Toxicity of PFHxA in Mice.

This article presents a supplemental data analysis and evaluation of the findings from an oral (gavage) combined developmental and perinatal/postnatal reproduction toxicity study of the ammonium salt of perfluorohexanoic acid (CASRN: 21615-47-4) in Crl: CD-1(ICR) mice. The original study has been cited as supporting a lowest-observed-adverse-effects level of 175 mg/kg/d and no-observed-adverse-effects level of 35 mg/kg/d for developmental effects from perfluorohexanoic acid (PFHxA, CASRN: 307-24-4) in mice. The statistical analysis reported in 2014 was accurate in terms of quantifying statistical significance within phase 2 of the study. However, given the low incidence of findings, the purpose of this article is to extend the analysis and interpretation of findings by pooling the control group information from both phases of the same study, comparing the study findings to the incidence rates for stillbirths and postpartum viability for this species and strain of mouse observed for similar studies conducted by the same laboratory, and evaluating data on the incidence and range of spontaneous eye abnormalities reported in the literature. Based on this supplemental evaluation, the original study supports a NOAEL of 175 mg/kg/d for PFHxA in mice, which is a factor of 5-fold higher than previously reported. Furthermore, to the extent that this study may be considered in the selection of a point of departure for PFHxA in mice, it is noted that 175 mg/kg/d for maternal exposure is an unbounded NOAEL for developmental effects, meaning that the study did not establish a dose at which developmental effects may occur.

Human-animal interactions and bat coronavirus spillover potential among rural residents in Southern China.

Human interaction with animals has been implicated as a primary risk factor for several high impact zoonoses, including many bat-origin viral diseases. However the animal-to-human spillover events that lead to emerging diseases are rarely observed or clinically examined, and the link between specific interactions and spillover risk is poorly understood. To investigate this phenomenon, we conducted biological-behavioral surveillance among rural residents in Yunnan, Guangxi, and Guangdong districts of Southern China, where we have identified a number of SARS-related coronaviruses in bats. Serum samples were tested for four bat-borne coronaviruses using newly developed enzyme-linked immunosorbent assays (ELISA). Survey data were used to characterize associations between human-animal contact and bat coronavirus spillover risk. A total of 1,596 residents were enrolled in the study from 2015 to 2017. Nine participants (0.6%) tested positive for bat coronaviruses. 265 (17%) participants reported severe acute respiratory infections (SARI) and/or influenza-like illness (ILI) symptoms in the past year, which were associated with poultry, carnivore, rodent/shrew, or bat contact, with variability by family income and district of residence. This study provides serological evidence of bat coronavirus spillover in rural communities in Southern China. The low seroprevalence observed in this study suggests that bat coronavirus spillover is a rare event. Nonetheless, this study highlights associations between human-animal interaction and zoonotic spillover risk. These findings can be used to support targeted biological behavioral surveillance in high-risk geographic areas in order to reduce the risk of zoonotic disease emergence.

Temporal Trends in Exposure to Organophosphate Flame Retardants in the United States.

During the past decade, use of organophosphate compounds as flame retardants and plasticizers has increased. Numerous studies investigating biomarkers (i.e., urinary metabolites) demonstrate ubiquitous human exposure and suggest that human exposure may be increasing. To formally assess temporal trends, we combined data from 14 U.S. epidemiologic studies for which our laboratory group previously assessed exposure to two commonly used organophosphate compounds, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP). Using individual-level data and samples collected between 2002 and 2015, we assessed temporal and seasonal trends in urinary bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), the metabolites of TDCIPP and TPHP, respectively. Data suggest that BDCIPP concentrations have increased dramatically since 2002. Samples collected in 2014 and 2015 had BDCIPP concentrations that were more than 15 times higher than those collected in 2002 and 2003 (10ß = 16.5; 95% confidence interval from 9.64 to 28.3). Our results also demonstrate significant increases in DPHP levels; however, increases were much smaller than for BDCIPP. Additionally, results suggest that exposure varies seasonally, with significantly higher levels of exposure in summer for both TDCIPP and TPHP. Given these increases, more research is needed to determine whether the levels of exposure experienced by the general population are related to adverse health outcomes.

Nail polish as a source of exposure to triphenyl phosphate.

Triphenyl phosphate (TPHP) is primarily used as either a flame retardant or plasticizer, and is listed as an ingredient in nail polishes. However, the concentration of TPHP in nail polish and the extent of human exposure following applications have not been previously studied. We measured TPHP in ten different nail polish samples purchased from department stores and pharmacies in 2013-2014. Concentrations up to 1.68% TPHP by weight were detected in eight samples, including two that did not list TPHP as an ingredient. Two cohorts (n=26 participants) were recruited to assess fingernail painting as a pathway of TPHP exposure. Participants provided urine samples before and after applying one brand of polish containing 0.97% TPHP by weight. Diphenyl phosphate (DPHP), a TPHP metabolite, was then measured in urine samples (n=411) and found to increase nearly seven-fold 10-14h after fingernail painting (p<0.001). To determine relative contributions of inhalation and dermal exposure, ten participants also painted their nails and painted synthetic nails adhered to gloves on two separate occasions, and collected urine for 24h following applications. Urinary DPHP was significantly diminished when wearing gloves, suggesting that the primary exposure route is dermal. Our results indicate that nail polish may be a significant source of short-term TPHP exposure and a source of chronic exposure for frequent users or those occupationally exposed.

Screening-level human health risk assessment of toluene and dibutyl phthalate in nail lacquers.

Toluene and dibutyl phthalate (DBP) are found in many consumer products, including cosmetics, synthetic fragrances, and nail polish. In 2012, the California Environmental Protection Agency evaluated 25 nail products and found that 83% of the products that claimed to be toluene-free contained toluene at concentrations ranging up to 190,000 ppm, and 14% of the products that claimed to be DBP-free contained DBP at concentrations ranging up to 88,000 ppm. We conducted a preliminary, screening-level analysis of the potential toluene and DBP-related health risks to consumers and professionals based on the medium and maximum concentrations of toluene and DBP presented in the 2012 report and evaluated dermal and inhalation exposure to a salon patron, nail technician, and home user. We concluded that the maximum toluene concentration for the technician and home user scenarios exceeded the California MADL, but the estimated air concentrations did not exceed the Federal or Cal OSHA PEL. The MADL for DBP was exceeded for all user scenarios at both the median and maximum concentrations. Using these highly conservative assumptions, exposures above regulatory limits could possibly occur during routine use of nail products; further research is needed in order to evaluate potential human health risks.