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Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.

BackgroundThe prevalence of obesity is increasing in all countries, becoming a substantial public health concern worldwide. Increasing evidence has associated obesity with persistent pollutants such as the pesticide DDT and its metabolite p,p'-DDE.ObjectivesOur objective was to systematically review the literature on the association between exposure to the pesticide DDT and its metabolites and obesity to develop hazard identification conclusions.MethodsWe applied a systematic review-based strategy to identify and integrate evidence from epidemiological, in vivo, and in vitro studies. The evidence from prospective epidemiological studies was quantitatively synthesized by meta-analysis. We rated the body of evidence and integrated the streams of evidence to systematically develop hazard identification conclusions.ResultsWe identified seven epidemiological studies reporting prospective associations between exposure to p,p'-DDE and adiposity assessed by body mass index (BMI) z-score. The results from the meta-analysis revealed positive associations between exposure to p,p'-DDE and BMI z-score (β=0.13 BMI z-score (95% CI: 0.01, 0.25) per log increase of p,p'-DDE). Two studies constituted the primary in vivo evidence. Both studies reported positive associations between exposure to p,p'-DDT and increased adiposity in rodents. We identified 19 in vivo studies and 7 in vitro studies that supported the biological plausibility of the obesogenic effects of p,p'-DDT and p,p'-DDE.ConclusionsWe classified p,p'-DDT and p,p'-DDE as "presumed" to be obesogenic for humans, based on a moderate level of primary human evidence, a moderate level of primary in vivo evidence, and a moderate level of supporting evidence from in vivo and in vitro studies. https://doi.org/10.1289/EHP527.

Background: Autism spectrum disorder is a diagnosis that is increasingly applied; however, previous studies have conflicting findings whether rates of diagnosis rates continue to grow in the UK. This study tested whether the proportion of people receiving a new autism diagnosis has been increasing over a twenty‐year period, both overall and by subgroups. Method: Population‐based study utilizing the Clinical Practice Research Datalink (CPRD) primary care database, which contains patients registered with practices contributing data to the CPRD between 1998 and 2018 (N = 6,786,212 in 1998 to N = 9,594,598 in 2018). 65,665 patients had a diagnosis of autism recorded in 2018. Time trend of new (incident) cases of autism diagnosis was plotted for all, and stratified by gender, diagnostic subtypes, and developmental stage: infancy and preschool, 0–5 years old; childhood, 6–11 years old; adolescence, 12–19 years old; adults, over 19 years old. Results: There was a 787%, exponential increase in recorded incidence of autism diagnoses between 1998 and 2018; R2 = 0.98, exponentiated coefficient = 1.07, 95% CI [1.06, 1.08], p <.001. The increase in diagnoses was greater for females than males (exponentiated interaction coefficient = 1.02, 95% CI [1.01, 1.03], p <.001) and moderated by age band, with the greatest rises in diagnostic incidence among adults (exponentiated interaction coefficient = 1.06, 95% CI [1.04, 1.07], p <.001). Conclusions: Increases could be due to growth in prevalence or, more likely, increased reporting and application of diagnosis. Rising diagnosis among adults, females and higher functioning individuals suggest augmented recognition underpins these changes. [ABSTRACT FROM AUTHOR]

The glomerular filtration barrier (GFB) is generally considered to consist of three layers: fenestrated glomerular endothelium, glomerular basement membrane, and filtration slits between adjacent podocyte foot processes. Detailed anatomic examination of the GFB has revealed a novel abluminal structure, the subpodocyte space (SPS), identified as the labyrinthine space between the underside of podocyte cell body/primary processes and the foot processes. The SPS covers 50-65% of the filtration surface of the GFB, indicating that SPS may influence glomerular permeability. We have examined the contribution of the SPS to the permeability characteristics of the GFB using multiphoton microscopy techniques in isolated, perfused glomeruli and in the intact kidney in vivo. SPS were identified using this technique, with comparable dimensions to SPS examined with electron microscopy. The passage of the intermediate-weight molecule rhodamine-conjugated 10-kDa dextran, but not the low-weight molecule lucifer yellow ([approximately equal to] 450 Da), accumulated in SPS-covered regions of the GFB, compared with GFB regions not covered by SPS ('naked regions'). Net lucifer yellow flux (taken to indicate fluid flux) through identifiable SPS regions was calculated to be 66-75% of that occurring through naked regions. These observations indicate both ultrafiltration and hydraulic resistance imparted by the SPS, demonstrating the potential physiological contribution of the SPS to glomerular permeability. glomerulus; permeability; podocyte; multiphoton

BACKGROUND: The [RD.sub.50] (exposure concentration producing a 50% respiratory rate decrease) test evaluates airborne chemicals for sensory irritation and has become an American Society for Testing and Materials (ASTM) standard method. Past studies reported good correlations ([R.sup.2]) between [RD.sub.50]s and the occupational exposure limits, particularly threshold limit values (TLVs). OBJECTIVE: The main purpose of this study was to examine the relationship between [RD.sub.50]s and human sensory irritation responses in a quantitative manner, particularly for chemicals that produce burning sensation of the eyes, nose, or throat, based on lowest observed adverse effect levels (LOAELs) reported for human subjects. METHODS: We compared [RD.sub.50]s with LOAELs and acute reference exposure levels (RELs). RELs, developed by the California Environmental Protection Agency&apos;s Office of Environmental Health Hazard Assessment, represent a level at which no adverse effects are anticipated after exposure. We collected [RD.sub.50]s from the published literature and evaluated them for consistency with ASTM procedures. We identified LOAELs for human irritation and found 25 chemicals with a corresponding [RD.sub.50] in mice. DISCUSSION: We found the relationship between [RD.sub.50]s and LOAELs as log [RD.sub.50] = 1.16 (log LOAEL) + 0.77 with an [R.sup.2] value of 0.80. This strong correlation supports the use of the [RD.sub.50] in establishing exposure limits for the public. We further identified 16 chemical irritants with both [RD.sub.50]s and corresponding acute RELs, and calculated the relationship as log [RD.sub.50] = 0.71 (log REL) + 2.55 with an [R.sup.2] value of 0.71. This relationship could be used to identify health protective values for the public to prevent respiratory or sensory irritation. CONCLUSION: Consequently, we believe that the [RD.sub.50] has benefits for use in setting protective levels for the health of both workers and the general population. KEY WORDS: Alarie test, exposure levels, LOAEL, [RD.sub.50], REL, sensory irritation, TLV. Environ Health Perspect 115:1609-1616 (2007). doi:10.1289/ehp.9848 available via http://dx.doi.org/ [Online 7 August 2007], Although airborne chemicals can cause a number of harmful effects, the most common effect is sensory irritation (De Ceaurriz et al. 1981). Exposure to a sensory irritant may stimulate the [...]