Current practice and recommendations for advancing how human variability and susceptibility are considered in chemical risk assessment.

A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Family relationships and familism among Mexican Americans on the U.S.-Mexico border during the COVID-19 pandemic.

OBJECTIVES: Coronavirus disease (COVID-19) has had a disproportionately negative impact on communities of color across the U.S., including Mexican Americans. The present study examined the influence of the pandemic on family relationships among individuals living in the U.S.-Mexico border region and how changes in family relationships were related to both familism values and mental health. METHOD: Two hundred ninety-one college Latino students participated in a survey that asked about changes in family relationships and mental health since the beginning of the pandemic. RESULTS: Contrary to our initial hypothesis, the majority of respondents indicated their family relationships had not changed since the beginning of the pandemic. However, those who reported negative changes in their family relationships also reported worse mental health whereas those who reported positive changes reported higher familism values. Mediational models revealed an indirect effect of familism support values on depression via changes in family relationships. CONCLUSIONS: Although cross-sectional, these results provide preliminary evidence of the impact of the COVID-19 pandemic on the mental health of Mexican Americans in the border region, as well as cultural factors that promote resilience in times of stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Response to: "letter to the editor regarding the article "the global distribution of acute unintentional pesticide poisoning: estimations based on a systematic review"" by Dunn et al. 2021 in BMC public health.

In a correspondence to BMC Public Health, Dunn et al. (Dunn SE, Reed J and Neumann C. BMC Public Health (n.d)) respond to our review on the occurrence of unintentional, acute pesticide poisoning (UAPP). Based on a systematic review and further data sources we estimated that about 385 million cases of UAPP occur annually world-wide including around 11,000 fatalities (Boedeker W. et al. BMC Public Health:1875, 2020).

The global distribution of acute unintentional pesticide poisoning: estimations based on a systematic review.

BACKGROUND: Human poisoning by pesticides has long been seen as a severe public health problem. As early as 1990, a task force of the World Health Organization (WHO) estimated that about one million unintentional pesticide poisonings occur annually, leading to approximately 20,000 deaths. Thirty years on there is no up-to-date picture of global pesticide poisoning despite an increase in global pesticide use. Our aim was to systematically review the prevalence of unintentional, acute pesticide poisoning (UAPP), and to estimate the annual global number of UAPP. METHODS: We carried out a systematic review of the scientific literature published between 2006 and 2018, supplemented by mortality data from WHO. We extracted data from 157 publications and the WHO cause-of-death database, then performed country-wise synopses, and arrived at annual numbers of national UAPP. World-wide UAPP was estimated based on national figures and population data for regions defined by the Food and Agriculture Organization (FAO). RESULTS: In total 141 countries were covered, including 58 by the 157 articles and an additional 83 by data from the WHO Mortality Database. Approximately 740,000 annual cases of UAPP were reported by the extracted publications resulting from 7446 fatalities and 733,921 non-fatal cases. On this basis, we estimate that about 385 million cases of UAPP occur annually world-wide including around 11,000 fatalities. Based on a worldwide farming population of approximately 860 million this means that about 44% of farmers are poisoned by pesticides every year. The greatest estimated number of UAPP cases is in southern Asia, followed by south-eastern Asia and east Africa with regards to non-fatal UAPP. CONCLUSIONS: Our study updates outdated figures on world-wide UAPP. Along with other estimates, robust evidence is presented that acute pesticide poisoning is an ongoing major global public health challenge. There is a need to recognize the high burden of non-fatal UAPP, particularly on farmers and farmworkers, and that the current focus solely on fatalities hampers international efforts in risk assessment and prevention of poisoning. Implementation of the international recommendations to phase out highly hazardous pesticides by the FAO Council could significantly reduce the burden of UAPP.

Relationship Between Cachexia and the Functional Progress of Patients With Cancer in Inpatient Rehabilitation.

PURPOSE: Although inpatient rehabilitation can improve functional independence in patients with cancer, the role of cachexia in this population is unknown. Our objectives were to:1) Establish prevalence of cachexia in a cohort of cancer patients receiving inpatient rehabilitation and its association with demographic and oncological history.2) Determine the relationship between the presence of cachexia and functional recovery and whether these patients in inpatient rehabilitation have a distinct prognosis. METHODS: This is a retrospective cohort study of 250 patients over 330 admissions to an inpatient rehabilitation facility. Body weight loss threshold and Weight Loss Grading Scale identified patients with and without cachexia. Main outcomes were functional independence measure scores, discharge destination, and 6-mo survival. RESULTS: Prevalence of cachexia in inpatient rehabilitation was 59% using consensus body weight loss criteria, and 77% of cancer patients had a Weight Loss Grading Scale score greater than 0. Patients with and without cachexia had similar motor and cognitive gains, although patients with severe cachexia had more limited functional gains ( P < 0.05) and increased odds of acute care return ( P < 0.01). Patients with a Weight Loss Grading Scale score of 4 had decreased survival at 6 mos ( P < 0.05) compared with noncachectic patients. CONCLUSIONS: These data suggest that there is a relationship between cachexia and recovery for cancer patients that should be further studied in rehabilitation settings.

Structural Evolution of Ultrathin SrFeO3-δ Films during Oxygen Evolution Reaction Revealed by In Situ Electrochemical Stress Measurements.

We report the electrochemical stress analysis of SrFeO3-δ (SFO) films deposited on Au substrates during oxygen evolution reactions (OERs). Our in situ analysis of Au reveals conversion reactions from Au to Au(OH)3, AuOOH, and AuOx during the OER. Au reactions cause a monotonic compressive stress on surfaces assigned to the formation of Au hydroxides and oxides. Electrochemical stress analysis of SrFeO3-δ/Au shows a dramatically different behavior during the OER, which we attribute to structural evolutions and conversion reactions, such as the conversion of SFO to iron (oxy)hydroxides. Interestingly, electrochemical stress analysis of SrFeO3-δ/Au shows a tensile trend, which evolves with cycling history. Electrochemical stress analysis of SFO films before the onset of the OER shows in situ changes, which cause tensile stresses when cycling to 1.2 V. We attribute these stresses to the formation of Fe2+δOδ(OH)2-δ (0 ≤ δ ≤ 1.5)-type materials where δ approaches 1.5 at higher potentials. At potentials higher than 1.2 V and during OER, surface stress response is rather stable, which we assign to the full conversion of SFO to iron (oxy)hydroxides. This analysis provides insight into the reaction mechanism and details of in situ structural changes of iron perovskites during the OER in alkaline environments.

Expression and functional analyses for estrogen receptor and estrogen related receptor of Yesso scallop, Patinopecten yessoensis.

Estrogen receptors (ERs) were known as estrogen-activated transcription factors and function as major reproduction regulators in vertebrates. The presence of er genes had been reported in Molluscan cephalopods and gastropods. However, they were considered as constitutive activators with unknown biological functions since reporter assays for these ERs did not show a specific response to estrogens. In this study, we tried characterization of ER orthologues from the Yesso scallop, Patinopecten yessoensis, in which estrogens had been proven to be produced in the gonads and involved in the spermatogenesis and vitellogenesis. Identified ER and estrogen related receptor (ERR) of Yesso scallops, designated as py-ER and py-ERR, conserved specific domain structures for a nuclear receptor. Their DNA binding domains showed high similarities to those of vertebrate ER orthologues, while ligand binding domains had low similarities with them. Both the py-er and py-err expression levels decreased in the ovary at the mature stage while py-vitellogenin expression increased in the ovary by quantitative real-time RT-PCR. Also, the py-er and py-err showed higher expressions in the testis than ovary during the developing and mature period, suggesting both genes might function in the spermatogenesis and testis development. The py-ER showed binding affinities to vertebrate estradiol-17ß (E2). However, the intensity was weaker than the vertebrate ER, indicating scallops might exist endogenous estrogens with a different structure. On the other hand, the binding property of py-ERR to E2 was not confirmed in this assay, speculating that py-ERR was a constitutive activator as other vertebrate ERRs. Further, the py-er was localized in the spermatogonia in the testis and in the auxiliary cells in the ovary by in situ hybridization, indicating its potential roles in promoting spermatogenesis and vitellogenesis. Taken together, the present study demonstrated that py-ER was an authentic E2 receptor in the Yesso scallop and might have functions for the spermatogonia proliferation and vitellogenesis, while py-ERR was involved in the reproduction by undiscovered manners.

Gait speed is a biomarker of cancer-associated cachexia decline and recovery.

Background: Progressive functional decline is a key element of cancer-associated cachexia. No therapies have successfully translated to the clinic due to an inability to measure and improve physical function in cachectic patients. Major barriers to translating pre-clinical therapies to the clinic include lack of cancer models that accurately mimic functional decline and use of non-specific outcome measures of function, like grip strength. New approaches are needed to investigate cachexia-related function at both the basic and clinical science levels. Methods: Survival extension studies were performed by testing multiple cell lines, dilutions, and vehicle-types in orthotopic implantation of K-ras LSL.G12D/+ ; Trp53 R172H/+ ; Pdx-1-Cre (KPC) derived cells. 128 animals in this new model were then assessed for muscle wasting, inflammation, and functional decline using a battery of biochemical, physiologic, and behavioral techniques. In parallel, we analyzed a 156-subject cohort of cancer patients with a range of cachexia severity, and who required rehabilitation, to determine the relationship between gait speed via six-minute walk test (6MWT), grip strength (hGS), and functional independence measures (FIM). Cachectic patients were identified using the Weight Loss Grading Scale (WLGS), Fearon consensus criteria, and the Prognostic Nutritional Index (PNI). Results: Using a 100-cell dose of DT10022 KPC cells, we extended the survival of the KPC orthotopic model to 8-9 weeks post-implantation compared to higher doses used (p<0.001). In this Low-dose Orthotopic (LO) model, both progressive skeletal and cardiac muscle wasting were detected in parallel to systemic inflammation; skeletal muscle atrophy at the fiber level was detected as early as 3 weeks post-implantation compared to controls (p<0.001). Gait speed in LO animals declined as early 2 week post-implantation whereas grip strength change was a late event and related to end of life. Principle component analysis (PCA) revealed distinct cachectic and non-cachectic animal populations, which we leveraged to show that gait speed decline was specific to cachexia (p<0.01) while grip strength decline was not (p=0.19). These data paralleled our observations in cancer patients with cachexia who required rehabilitation. In cachectic patients (identified by WLGS, Fearon criteria, or PNI, change in 6MWT correlated with motor FIM score changes while hGS did not (r 2 =0.18, p<0.001). This relationship between 6MWT and FIM in cachectic patients was further confirmed through multivariate regression (r 2 =0.30, p<0.001) controlling for age and cancer burden. Conclusion: Outcome measures linked to gait are better associated with cachexia related function and preferred for future pre-clinical and clinical cachexia studies.

Placentation in watersnakes II: Placental ultrastructure in Nerodia erythrogaster (Colubridae: Natricinae).

Ultrastructure of the placental tissues from redbelly watersnakes (Nerodia erythrogaster) was analyzed during late pregnancy to provide insight into placental development and function. Examination of the chorioallantoic placenta with transmission electron microscopy reveals that chorionic and uterine epithelia are extremely attenuated but intact and that the eggshell membrane is vestigial and lacks a calcareous layer. These features minimize the interhemal diffusion distance across the placenta. Scanning electron microscopy reveals that fetal and maternal components of the placentas are richly vascularized by dense networks of capillaries. Although the yolk sac omphalopleure has largely been replaced by chorioallantois by late gestation, it retains patches of yolk droplets and regions of absorptive cells with microvilli and abundant mitochondria. Transmission electron microscopy reveals that yolk material is taken up for digestion by endodermal cells. As yolk is removed, allantoic capillaries invade to occupy positions just beneath the epithelium, forming regions of chorioallantoic placentation. Ultrastructural features indicate that the chorioallantoic placenta is specialized for gas exchange, while the omphalallantoic ("yolk sac") placenta shows evidence of functions in yolk digestion and maternal-fetal nutrient transfer. Placental features of this species are consistent with those of other thamnophines, and are evolutionarily convergent on snakes of other viviparous clades.

Isolation of estrogen receptor subtypes and vitellogenin genes: expression in female Chalcalburnus tarichi.

Reproductively arrested gonadal development has been previously described in the teleost pearl mullet (Chalcalburnus tarichi, Cyprinidae) from Van Edremit Gulf of Lake Van, Turkey. Oocyte development in some females was arrested at the previtellogenic stage, while gonadosomatic index (GSI) and plasma 17ß-estradiol (E2) level were low. A subset of the females was found to have normal ovaries and relatively higher plasma E2 and GSI. These two groups were termed reproductively arrested (RA) and reproductively non-arrested (RN) females. In this study, we cloned estrogen receptor (ER) isoforms (ERα, ERß1 and ERß2) and vitellogenin (Vtg), and their mRNA levels were measured in RA and RN fish tissues. C. tarichi ERs fell in the same clade with other fish ERs and ERα and ERß1 had 97% and 98% identity with the roach (Rutilus rutilus) ERs, respectively. Both Vtg and ER isoforms' mRNA abundance were higher in the liver than in the ovary and hypothalamus (liver>ovary>hypothalamus). The level of ERα mRNA was significantly lower in the liver, ovary and brain of RA fish than in the RN fish tissues. ERß1 mRNA levels were not different in the liver and ovary from RA and RN fish while ERß2 expression significantly increased in the liver and ovary from RA fish. All ER subtype expression was found to be lower in the brain from RA fish than RN fish. The level of Vtg mRNA was significantly lower in the liver and ovary from RA fish than RN fish tissue. These results suggest that ER subtypes are differentially regulated by E2, and their functions are also different in vitellogenesis. Analysis of organic contaminants in sediments revealed that C. tarichi living in Van Edremit Gulf of Lake Van are exposed to the contaminants bis(2-ethylhexyl) phthalate and 4,4(') DDT. We suggest that the RA fish represent a segment of the population that is more sensitive to exposure to endocrine disrupting compounds.

Cloning of estrogen receptor alpha and aromatase cDNAs and gene expression in turtles (Chrysemys picta and Pseudemys scripta) exposed to different environments.

Reproductive changes have been observed in painted turtles (Chrysemys picta) from a site with known contamination located on Cape Cod, MA, USA. We hypothesize that these changes are caused by exposure to endocrine-disrupting compounds and that genes playing a significant role in reproduction are affected. cDNA sequences were determined for estrogen receptor alpha and aromatase in the painted turtle. These genes were measured in our study animals using quantitative PCR. Adult turtles were trapped from our study site (Moody Pond, MP) or a reference site (Washburn Pond) and exposed to laboratory environments containing soil from either site. The red-eared slider (Pseudemys scripta), a pond turtle closely related to the painted turtle, was used to assess neonatal exposure to soil and water from the sites. Our results show an increase in hepatic estrogen receptor, which suggests exposure to estrogenic contaminants. Female turtles from MP appear to have a long-term effect on hepatic ER. Other findings were apparent age-dependent differences in expression of aromatase and ER in the brains of neonate and year-old juvenile turtles. Phylogenetic analyses of the cDNA sequences further support the hypothesis that turtles are in a sister clade to birds and crocodilians.

Novel cDNA sequences of aryl hydrocarbon receptors and gene expression in turtles (Chrysemys picta and Pseudemys scripta) exposed to different environments.

Reproductive changes have been observed in painted turtles from a site with known contamination located on Cape Cod, MA, USA. We hypothesize that these changes are caused by exposure to endocrine-disrupting compounds and that genes involved in reproduction are affected. The aryl hydrocarbon receptor (AHR) is an orphan receptor that is activated by environmental contaminants. AHR mRNA was measured in turtles exposed to soil collected from a contaminated site. Adult turtles were trapped from the study site (Moody Pond, MP) or a reference site and exposed to laboratory environments containing soil from either site. The red-eared slider was used to assess neonatal exposure to soil and water from the sites. The environmental exposures occurred over a 13-month period. Juveniles showed an age-dependent increase in brain AHR1. Juvenile turtles exposed to the MP environment had elevated gonadal AHR1. Adult turtles exposed to the MP environment showed significantly decreased brain AHR2. The painted turtle AHR is the first complete reptile AHR cDNA sequence. Phylogenetic analysis of the painted turtle AHR showed that it clusters with other AHR2s. Partial AHR1 and partial AHR2 cDNA sequences were cloned from the red-eared slider. MEME analysis identified 18 motifs in the turtle AHRs, showing high conservation between motifs that overlapped functional regions in both AHR isoforms.