INTRODUCTION:In bipolar women who took lithium during pregnancy, several epidemiology studies have reported small increases in a rare fetal cardiac defect termed Ebstein's anomaly.METHODS:Behavioral, environmental, and lifestyle-associated risk factors associated with bipolar disorder and health insurance status were determined from an Internet search. The search was conducted from October 1, 2023, through October 14, 2023. The search terms employed included the following: bipolar, bipolar disorder, mood disorders, pregnancy, congenital heart defects, Ebstein's anomaly, diabetes, hypertension, Medicaid, Medicaid patients, alcohol use, cigarette smoking, marijuana, cocaine, methamphetamine, narcotics, nutrition, diet, obesity, body mass index, environment, environmental exposures, poverty, socioeconomic status, divorce, unemployment, and income. No quotes, special fields, truncations, etc., were used in the searches. No filters of any kind were used in the searches.RESULTS:Women who remain on lithium in the United States throughout their pregnancy are likely to be experiencing mania symptoms and/or suicidal ideation refractory to other drugs. Pregnant women administered the highest doses of lithium salts would be expected to have been insufficiently responsive to lower doses. Any small increases in the retrospectively determined risk of fetal cardiac anomalies in bipolar women taking lithium salts cannot be disentangled from potential developmental effects resulting from very high rates of cigarette smoking, poor diet, alcohol abuse, ingestion of illegal drugs like cocaine or opioids, marijuana smoking, obesity, and poverty.CONCLUSIONS:The small risks in fetal cardiac abnormalities reported in the epidemiology literature do not establish a causal association for lithium salts and Ebstein's anomaly.

Epidemiological evidence of an association between exposure to chemical carcinogens and an increased risk for development of glioblastoma (GBM) is limited to weak statistical associations in cohorts of firefighters, farmers, residents exposed to air pollution, and soldiers exposed to toxic chemicals (e.g., military burn pits, oil-well fire smoke). A history of ionizing radiation therapy to the head or neck is associated with an increased risk of GBM. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Data on 16 agents (15 chemicals and radio frequency radiation) that induced tumors in the rodent brain were extracted from 602 Technical Reports on 2-years cancer bioassays found in the National Toxicology Program database. Ten of the 15 chemical agents that induce brain tumors are alkylating agents. Three of the 15 chemical agents have idiosyncratic structures and might be alkylating agents. Only two of the 15 chemical agents are definitively not alkylating agents. The rat model is thought to be of possible relevance to humans suggesting that exposure to alkylating chemicals should be considered in epidemiology studies on GBM and other brain tumors.

The reported risk factors for glioblastoma (GBM), i.e., ionizing radiation, Li-Fraumeni syndrome, Neurofibromatosis I, and Turcot syndrome, also increase the risk of other brain tumor types. Risk factors for human GBM are associated with different oncogenic mutation profiles. Pedigreed domestic dogs with a shorter nose and flatter face (brachycephalic dogs) display relatively high rates of glioma formation. The genetic profiles of canine gliomas are also idiosyncratic. The association of putatively different mutational patterns in humans and canines with GBM suggests that different oncogenic pathways can result in GBM formation. Strong epidemiological evidence for an association between exposure to chemical carcinogens and an increased risk for development of GBM is currently lacking. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Weak statistical associations between chemical exposures and GBM reported in epidemiology studies are biologically plausible. Molecular approaches comparing reproducible patterns seen in spontaneous GBM with analogous patterns found in GBMs resected from patients with known significant exposures to potentially carcinogenic chemicals can address difficulties presented by traditional exposure assessment.

Fortea et al.’s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer’s disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD.

Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE) ɛ4/ɛ4 genotype, when the ɛ3 allele mutated from the ancestral ɛ4, which elevates the risk of Alzheimer's disease. Modern humans living today predominantly carry the ɛ3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral ɛ4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection pressure. Some bacteria can exploit the host's defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in ɛ4 carriers, yet ɛ4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the ɛ3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer's disease.

Roughly 6.5 million people in the United States have Alzheimer’s Disease and while there are a number of risk factors for developing the disease, the second largest risk factor comes from Apolipoprotein E. This protein plays a central role in fat metabolism. Alleles of the APOE gene can have a significant impact on an individual’s likelihood of developing Alzheimer’s. This article explores the value of genetic testing for this particular risk factor.

Gain of function research is a little known and controversial area of study in virology. Though there is some disagreement in the exact definition of gain of function, the process involves modifying animal viruses to infect human cells for the purposes of advancing the understanding of the way viruses mutate. This article examines the controversy, with particular consideration of the COVID-19 lab leak hypothesis, exploring the danger of creating such modified viruses.

Chemicals possessing persistence (P) and high mobility (M) can present a hazard to drinking water resources by traversing natural barriers like riverbanks and artificial barriers found in water treatment plants. If the chemical is also toxic (T), i.e. classifiable as a PMT, the agent might be of particular concern as a potential drinking water contaminant. During routine water sampling, detection and quantitation of polar substances with high mobility can be problematic. The German Environment Agency (UBA) is considering the use of the Log Koc value as a proxy for mobility (M). Log Koc is related to Log P by the equation Log Koc = 0.69 Log P + 0.22. In this study, we demonstrate that chemicals with log P values at or very close to 2.0, 3.0 or 4.0 (and their concomitant log Koc values) can vary significantly in their chemical structures, molecular weights, molar volumes, and calculated molar refractivity (CMR), which is related to the mean polarizability of a molecule. The large degree of potential diversity in chemical structure and molecular parameters related to chemical behavior at a particular log P or log Koc value suggests that log Koc might not contain enough information to function as a standalone surrogate for the mobility (M) of a chemical, i.e. as related to its ability to move from a drinking water resource through the water plant purification process.

In 2014, it was estimated that more than 1.9 billion adults were overweight with over 600 million classifiable as obese. Approximately two-thirds of U.S. adults over 20 years of age are currently overweight with about 35% classified as obese, a figure thought likely to reach 42% by 2030 in those over 18 years of age. Adipose cells from stored body fat secrete estrogen and a very large number (> 500) of biologically active substances termed adipokines, in addition to inducing, by other cell-driven effects, pathological alterations in insulin pathways. The U.S. National Cancer Institute reports that exposure to the hormone disrupting and proinflammatory effects of excess adipose tissue are associated with an increased risk for 11 different cancers. Obesity is also associated with a number of serious non-neoplastic conditions including metabolic syndrome and type 2 diabetes; menstrual cycle irregularities and lowered fertility (men and women); and abnormal bone morphology in a subset of female patients. In men hypogonadism, low testosterone levels, benign prostatic hyperplasia, and lowered sperm counts have been reported. In developed countries, the endogenous adverse health burden associated with obesity is only matched, quantitatively and qualitatively, by the exogenous toxicity of cigarette smoking. The investigation of possible hormonal and/or proinflammatory effects of chemicals should include an assessment of the profound endocrine alterations associated with obesity.

The maximum tolerated dose (MTD) provides the highest probability of a positive result in a toxicology bioassay. The assumption underlying the MTD in animal bioassays is that adverse effects at very high doses are qualitatively the same as those occurring at low doses. In contrast with the MTD, the optimal top dose in a toxicology animal study is the highest dose that does not produce a pathological end point that presents no risk at lower doses, for example, the dose below which cytotoxicity induces tumors in the absence of genotoxicity or other carcinogenic mechanisms. Normal concentrations or biological activity levels of many substances necessary for normal physiological function induce pathology when found at high levels. For example, the demonstration that ingestion of abnormally high levels of certain dietary fats can cause or exacerbate atherosclerosis in relevant animal models like rhesus macaques does not demonstrate that normal levels of these fats should be considered as toxic. Excessive estrogenic stimulation is associated with breast, ovarian, and endometrial cancers. This does not imply that normal age-appropriate levels of estrogen are toxic. Normal wound healing is associated with transforming growth factors beta 1 and 2. Excessive stimulation of fibroblasts by these growth factors results in hypertrophic scarring and keloid formation. An understanding of the mode of action of a test substance can facilitate the selection of dose levels much higher than those expected to be experienced by humans, but not beyond a dose level at which pathology is an experimental artefact of the high-dose level.

The immobility of plants exerted evolutionary selection pressures resulting in the production of thousands of chemical substances thought to function as pesticides against predation by insects and animals. More than 10,000 plant-derived compounds have been isolated with the existence of about 100,000 such compounds postulated. In 1990, Ames et al. reported that 99.99% by weight of the pesticides ingested in a normal human diet are derived from natural plant-based sources. This surprising result raised the question as to whether these natural plant pesticides were toxic to humans. These authors examined a relatively small subset of natural pesticides and determined that their tumorigenicity in rodent cancer bioassays was similar to synthetic pesticides. In this analysis, we used standard United States Environmental Protection Agency programs to estimate the toxicity (T.E.S.T. 4.2) and persistence (EPI Suite 4.1) of a series of high-volume synthetic and natural pesticides. On average, synthetic pesticides were more persistent in the environment than were natural pesticides. This result is consistent with cost, time, and logistical constraints under which farmers apply a limited number of applications of pesticides during a crop cycle. Synthetic and natural pesticides are predicted to possess toxicities including mutagenicity and developmental toxicity. Synthetic pesticides are less often mutagenic.

The bacterial reverse mutation assay, that is, the Ames test, measures mutations that reverse the inactivation of a gene involved in the synthesis of either histidine in Salmonella bacteria or tryptophan in Escherichia coli . The classic dose–response curve of an Ames assay plots number of reverse mutations (“revertants”) on the y -axis versus dose of the test chemical on the x -axis. Frequently, the dose–response curve resembles a parabola with a linear initial slope resulting from the accumulation of mutations, which transitions to a downward curvature resulting from cell killing (cytotoxicity) at increasingly higher doses of the test chemical. For regulatory purposes, a positive Ames test is usually considered as induction of twice the number of reverse mutations above background levels. For research purposes, the potency of the mutagenic response can be calculated from measuring the initial slope of the mutagenic response. This initial slope can be calculated in a manner that disentangles the downward pull on the initial slope value provided by the initiation of cytotoxicity. For a dose–response curve resembling a parabola, both the initial positive slope representing mutagenicity and the secondary negative slope representing cytotoxicity can be calculated from the same dose–response curve. The Ames test is the most commonly conducted genotoxicity assay. When a series of molecular congeners are assayed in the Ames test for mutagenicity, additional consideration of the cytotoxicity can provide important structure–activity relationship information.

Background: Obesity is a worldwide epidemic with approximately two billion adults classifiable as overweight and over 600 million as obese. In the US, approximately two-thirds of adults over age 20 are overweight with about 35% currently obese with the obesity percentage steadily rising. Aim: Obesity is a complex disease wherein an excessive amount of body fat accumulates from ingesting more calories than are burned. Obesity usually results from a combination of factors including genetics, ready availability of inexpensive high caloric foods, low exercise levels or sedentary lifestyles, and poor dietary choices. Methods: This paper provides an overview of the available information on synthetic endocrine disrupter chemicals and reasons why these chemicals are not a significant cause of obesity. Results: Prenatal effects of exposure to synthetic endocrine disrupting chemicals (EDCs) have been proposed as a causative factor in the obesity epidemic. Population effects from prenatal EDCs would be expected to be very minor as exposures to EDCs are very low; and humans are routinely exposed to a huge number and high concentration of naturally occurring chemicals with potential endocrine effects. Further reducing exposures to the trace amounts of EDCs in the environment would not be expected to measurably ameliorate the obesity epidemic which is mainly being driven by excessive caloric intake of high carbohydrate and high sugar content foods. Conclusions: While exposure to synthetic EDCs is not a major factor in developing obesity, the converse is true; adipose tissue is an important source of estrogens, testosterone, thyroid stimulating hormone, leptin and approximately 500 biologically active compounds termed adipokines. The hormonal and pro-inflammatory effects of adipose tissue underlie the association between obesity and increased risk of a number of chronic diseases.

Dr. Bruce Ames turned 92 on December 16, 2020. He considers his most recent work linking adequate consumption of 30 known vitamins and minerals with successful aging to be his most important contribution. With the passage of time, it is not uncommon for the accomplishments of a well-known scientist to undergo a parsimonious reductionism in the public mind - Pasteur's vaccine, Mendel's peas, Pavlov's dogs, Ames' test. Those of us in the research generation subsequent to Dr. Ames' are undoubtedly affected by our own unconscious tendencies toward accepting the outstanding achievements of the past as commonplace. In doing so, seminal advances made by earlier investigators are often inadvertently subsumed into common knowledge. But having followed Ames' work since the mid-1970s, we are cognizant that the eponymous Ames Test is but a single chapter in a long and rich narrative. That narrative begins with Ames' classic studies on the histidine operon of Salmonella, for which he was elected to the National Academy of Sciences. A summary of the historical progression of the understanding of chemical carcinogenesis to which Ames and his colleagues contributed is provided. Any summary of a topic as expansive and complex as the ongoing unraveling of the mechanisms underlying chemical carcinogenesis will only touch upon some of the major conceptual advances to which Ames and his colleagues contributed. We hope that scientists of all ages familiar with Ames only through the eponymous Ames Test will further investigate the historical progression of the conceptualization of cancer caused by chemical exposure. As the field of chemical carcinogenesis gradually moves away from primary reliance on animal testing to alternative protocols under the rubric of New Approach Methodologies (NAM) an understanding of where we have been might help to guide where we should go.

Exposure to chemicals produced by natural processes is ubiquitous. First, in addition to the products of normal metabolism produced in humans of normal body weight, adipose tissue produces a large number of chemicals, including estrogen, testosterone from the produced estrogen, thyroid-stimulating hormone, leptin and approximately 500 other molecules termed adipokines, and a large number of inflammatory mediators. Second, the gut biome contains approximately the same number of bacteria as cells found in the entire body and produces a large number of small molecules. Third, the overwhelming majority (99.9%) of pesticide exposure occurs during ingestion of natural plant pesticides from eating vegetables. Fourth, consumption of cooked muscles meats leads to significant exposure to mutagenic and carcinogenic heterocyclic amines, polycyclic aromatic amines, and nitropyrenes. Fifth, many common beverages, for example, beer, coffee, and tea contain organic chemicals that display mutagenic activity. As compared with man-made production levels, from 1945 to 2015, an estimated 5000-fold more organic compounds were produced by a variety of natural processes, including common wood-degrading and forest litter-degrading fungi, microorganisms in temperate and boreal forest soils, bacteria in marine sponges, marine macro-algae, volcanoes, and forest fires. Exposure to these naturally produced organic compounds occurs via inhalation of ambient air, ingestion of food and water, and contact with soil, freshwater, and seawater. Contact with several thousand different endogenous or exogenous chemicals per day is unavoidable. This understanding might assist in better allocating resources toward controlling exposures to agents of highest concern as determined by current concepts of chronic disease causation.

Historical control data (HCD) consist of pooled control group responses from bioassays. These data must be collected and are often used or reported in regulatory toxicology studies for multiple purposes: as quality assurance for the test system, to help identify toxicological effects and their effect-size relevance and to address the statistical multiple comparison problem.The current manuscript reviews the various classical and potential new approaches for using HCD. Issues in current practice are identified and recommendations for improved use and discussion are provided. Furthermore, stakeholders are invited to discuss whether it is necessary to consider uncertainty when using HCD formally and statistically in toxicological discussions and whether binary inclusion/exclusion criteria for HCD should be revised to a tiered information contribution to assessments.Overall, the critical value of HCD in toxicological bioassays is highlighted when used in a weight-of-evidence assessment.

Ten years ago, the Halogenated Solvents Industry Alliance (HSIA) and the New York State Department of Environmental Conservation petitioned the US Environmental Protection Agency (USEPA) to classify 1-bromopropane (1-BP) as a hazardous air pollutant (HAP), the first such classification of a chemical since 1990. The USEPA plans to classify 1-BP as a HAP. One of the putative exposures supporting HAP classification is 1-BP-based dry cleaning solvents. Only two 1-BP-based dry cleaning solvents have ever been marketed domestically, i.e. the dominant market share product DrySolv® (DrySolv) and less commonly used Fabrisolv TM XL (Fabrisolv). The use of 1-BP-based dry cleaning solvents has been declining for several years. Fabrisolv is no longer marketed as a dry cleaning agent. In the first half of 2020, less than 1,600 pounds of DrySolv have been sold for the remaining six dedicated dry cleaning machines still in operation in the United States. It is expected that the number of dedicated DrySolv dry cleaning machines in operation will be reduced to three by the end of 2020. In addition, no 1-BP-based spot cleaner has ever been marketed in the United States. USEPA currently classifies 187 chemicals as HAPs, with a subset of 30 HAPS classified as urban air toxics. Dry cleaning is considered to be one of the 68 “area sources” that contribute to sub-classification of 1-BP as an urban air toxic. In the near future, 1-BP-based products will not be employed in the dry cleaning industry.

Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially reported in Wuhan, China in December 2019 was first detected in the United States on January 20, 2020 in a long-term care facility near Seattle, Washington. The virus spread quickly, and the World Health Organization declared a pandemic on March 11, 2020. On September 30, 2020 there were over 33.8 million cases and 1,013,000 deaths worldwide (130 deaths/million, 7.8 billion people), and over 7 million confirmed cases and 207,000 deaths in the United States (621 deaths/million, 333 million people) (data sources; for review, see Yamamoto et al1Yamamoto V Bolanos JF Fiallos J et al.COVID-19: review of a 21st century pandemic from etiology to neuro-psychiatric implications.J Alzheimers Dis. 2020; 77: 459-504Crossref PubMed Scopus (55) Google Scholar). The virus has high infectivity, with rapid contagion related to conditions favoring airborne spread, for example, congregate living facilities, long-term care facilities, and prisons. Traditional measures of social isolation (distancing), sanitation (hand washing/masks), and contact tracing have been implemented with variable success. However, 3 characteristics of COVID-19: 1) international variation; 2) age-related mortality; and 3) sequence homology between the fusion proteins of SARS-CoV-2 and measles and mumps viruses, and sequence homology between the Macro domains of SARS-CoV-2 and the rubella virus, suggest the Measles-Mumps-Rubella (MMR) vaccine may mitigate COVID-19 spread and severity. 1) COVID-19 has severely affected some countries and spared others. On September 30, 2020, China reported only 90,545 cases and 4739 deaths. Most deaths were in Hubei Province (population 59 million; 4512 deaths; 79 deaths/million), whose capital is Wuhan. Outside of Hubei Province, China (population nearly 1.4 billion) has reported only 227 deaths (0.16 deaths/million). China and the 36 other countries and regions in the World Health Organization Western Pacific Region (WPR) have the fewest cases and deaths per population unit. Most countries in Asia and Africa also have low COVID-19 rates. By contrast, the United States, other countries of the Americas, and Europe, have >50 times the death rate of WPR countries. Measles epidemics leading to measles elimination programs with mass MMR vaccination may explain part of the observed international variations, suggesting that MMR vaccine may provide strong protection from COVID-19 spread and mortality (first reported by Gold et al2Gold JE Tilley LP Baumartil WH MMR vaccine appears to confer strong protection from COVID-19: few deaths from SARS-CoV-2 in highly vaccinated populations.ResearchGate. 2020; (Available at:)https://www.researchgate.net/publication/341354165_MMR_Vaccine_Appears_to_Confer_Strong_Protection_from_COVID-19_Few_Deaths_from_SARS-CoV-2_in_Highly_Vaccinated_PopulationsDate accessed: October 26, 2020Google Scholar in March 2020; see also Franklin et al3Franklin R Young A Neumann B et al.Homologous protein domains in SARS-CoV-2 and measles, mumps, and rubella viruses: preliminary evidence than MMR vaccine might provide protection against COVID-19.medRxiv. 2020; (Available at)https://www.medrxiv.org/content/10.1101/2020.04.10.20053207v1.full.pdfDate accessed: October 26, 2020Google Scholar). Supporting the potential anti-COVID-19 benefit of MMR vaccine, the WPR has successfully reduced measles through extensive MMR vaccination programs.4Ma C Rodewald L Hao L et al.Progress toward measles elimination - China, January 2013-June 2019.MMWR Morb Mortal Wkly Rep. 2019; 68: 1112-1116Crossref PubMed Scopus (32) Google Scholar There are similar reports of measles epidemics and eradication efforts from other parts of Asia and across Africa. By contrast, MMR vaccination programs have been problematic in the United States,5Qian M Chou SY Lai EK Confirmatory bias in health decisions: evidence from the MMR-autism controversy.J Health Econ. 2020; 70102284Crossref PubMed Scopus (13) Google Scholar the rest of the Americas, and Europe.6Siciliani L Wild C McKee M et al.Strengthening vaccination programmes and health systems in the European Union: a framework for action.Health Policy. 2020; 124: 511-518Crossref PubMed Scopus (54) Google Scholar While travel restrictions, control of congregate living conditions, and governmental interventions play roles in controlling the COVID-19 spread, it is possible that MMR vaccination programs are the basis for the huge international variation. 2) In the United States, COVID-19 penetration has been extensive. Across all states, disease severity and mortality has been worst in the elderly, from the first reported deaths in nursing homes in Washington State until the present. Early deaths occurred at the end of March, peaked between mid-April and mid-May, then decreased prior to surging through July. While the number of deaths varied, the actual proportion of deaths related to COVID-19 across age groups changed very little (Centers for Disease Control [CDC] data). On September 30, 2020 the CDC reported 194,091 deaths, categorized by age and sex. Of these deaths, 20 were under 1 year of age and 47 were between 1 and 15 years (0.035% of all COVID-19 deaths, 60 million children, 1.1 deaths/million). All individuals under 45 years of age (190 million) accounted for <3% of the deaths (5898; 31 deaths/million), but those over 45 years (135 million) accounted for more than 97% of the deaths (188,193; 1394 deaths/million). After a large jump from 5 to 20 years of age, the death rate increased for those over age 30 years at an exponential age-related rate, doubling every 7.4 years. This rate exceeds the base rate of the exponential increase of total deaths with age (only doubling every 9 years after age 30, see Ashford7Ashford JW APOE genotype effects on Alzheimer's disease onset and epidemiology.J Mol Neurosci. 2004; 23: 157-165Crossref PubMed Scopus (201) Google Scholar). Accordingly, the vulnerability to COVID-19 is closely related to age but exceeds the increase of the established comorbid illnesses (obesity, hypertension, diabetes, vascular disease) with age. Unexpectedly, the percentage of COVID-19 deaths relative to all deaths increases most sharply between 15 and 45 years, but over 45 there is a relatively stable percentage of COVID-19 deaths in this older population, ranging between 8.4% and 9.8%. This discrepancy suggests that the strong relationship with comorbidities occurs because of a confound with age, while some other factor is causally involved. As observed internationally, MMR vaccination could also potentially contribute to the US age distribution. The low infection rates and mild presentations in children >1 year of age may be due to childhood vaccinations. The CDC recommends that children get 2 MMR doses, at 12-15 months of age and 4-6 years. Double childhood MMR vaccination can generate antibodies lasting for 20 or more years.8Davidkin I Jokinen S Broman M Leinikki P Peltola H Persistence of measles, mumps, and rubella antibodies in an MMR-vaccinated cohort: a 20-year follow-up.J Infect Dis. 2008; 197: 950-956Crossref PubMed Scopus (266) Google Scholar Yet, some children do not get vaccinated at all.5Qian M Chou SY Lai EK Confirmatory bias in health decisions: evidence from the MMR-autism controversy.J Health Econ. 2020; 70102284Crossref PubMed Scopus (13) Google Scholar Further, long-term benefit declines with age, as evidenced by many women presenting for prenatal care who have lost MMR-related immunity.9Haas DM Flowers CA Congdon CL Rubella, rubeola, and mumps in pregnant women: susceptibilities and strategies for testing and vaccinating.Obstet Gynecol. 2005; 106: 295-300Crossref PubMed Scopus (34) Google Scholar This pattern is consistent with the observed progressive increase of COVID-19 infection and death rates up to 45 years of age (CDC data). The stabilization of the percentage increase in COVID-19 mortality with more advanced age may be due to long-lasting immune responses to now-rare childhood infections,10Mina MJ Kula T Leng Y et al.Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens.Science. 2019; 366: 599-606Crossref PubMed Scopus (232) Google Scholar but which are less protective against COVID-19. 3) There are reports that appear to suggest that several currently available vaccines already established as "safe" (including polio, Haemophilus influenzae type-B, MMR, and pneumococcal) may offer significant protection against COVID-19 via a nonspecific "innate immunity."11Fidel Jr, PL Noverr MC Could an unrelated live attenuated vaccine serve as a preventive measure to dampen septic inflammation associated with COVID-19 infection?.mBio. 2020; 11: e00907-e00920Crossref PubMed Scopus (78) Google Scholar, 12Pawlowski C Puranik A Bandi H et al.Exploratory analysis of immunization records highlights decreased SARA-CoV-2 rates in individuals with recent non-COVID-19 vaccinations.medRxiv. 2020; (Available at:)https://www.medrxiv.org/content/10.1101/2020.07.27.20161976v1.full.pdfDate accessed: October 26, 2020Google Scholar, 13Root-Bernstein R Age and location in severity of COVID-19 pathology: do lactoferrin and pneumococcal vaccination explain low infant mortality and regional differences?.Bioessays. 2020; (Available at:)https://onlinelibrary.wiley.com/doi/full/10.1002/bies.202000076Date accessed: October 26, 2020Crossref PubMed Scopus (33) Google Scholar However, these findings may actually be reflecting a response to MMR vaccination, which is often administered in conjunction with these others. More directly, there is evidence that rubella virus has a 29% sequence homology with a SARS-CoV-2 surface protein.3Franklin R Young A Neumann B et al.Homologous protein domains in SARS-CoV-2 and measles, mumps, and rubella viruses: preliminary evidence than MMR vaccine might provide protection against COVID-19.medRxiv. 2020; (Available at)https://www.medrxiv.org/content/10.1101/2020.04.10.20053207v1.full.pdfDate accessed: October 26, 2020Google Scholar,14Sidiq KR Sabir DK Ali SM Kodzius R Does early childhood vaccination protect against COVID-19?.Front Mol Biosci. 2020; 7: 120Crossref PubMed Scopus (40) Google Scholar Accordingly, the rubella component of the MMR vaccine may confer specific protection against COVID-19. These findings suggest the MMR vaccine may protect against COVID-19, including high-risk individuals, such as elderly with comorbidities, and health care workers and first responders with COVID-19 patients, especially individuals living in long-term care facilities and the related institutional staff. Clinicians who are caring for such high-risk patients should consider the benefit/cost ratios of MMR vaccination to justify use of this simple, low-risk intervention to reduce COVID-19 disease, especially until a specific vaccine is approved. Clinical trials to confirm this speculation are now being conducted. Data Sources, most recently accessed 9/30/2020: Center for Disease Control and Prevention (CDC): www.cdc.gov United States Census Bureau: www.census.gov Worldometer: https://www.worldometers.info/coronavirus Johns Hopkins Coronavirus Resource Center: https://coronavirus.jhu.edu/map.html

Obesity as determined by BMI is a confounder in clinical evaluations of the effects of endocrine disrupting chemicals (EDCs). Validated regulatory tests are used to determine whether a chemical acts via a mode of action (MOA) that affects estrogen, androgen, thyroid or steroidogenic pathways. Test batteries for evaluating EDCs include QSAR, in vitro assays, and animal testing. Studies suggest that EDCs pose the greatest risk during prenatal and early infant development when organ systems are developing. Health effects include lowered fertility, endometriosis, and cancers associated with estrogenic activity. Epidemiology studies on adverse effects of EDCs in the general population are difficult to conduct due to very low exposures of EDCs in non-occupational cohorts, and lack of exposure measurements between cases and controls. In contrast with very low levels of hormonal perturbation from nano-molar to micro-molar exposures to EDCs, adipose tissue in obesity alters estrogen, testosterone, thyroid stimulating hormone, and inflammation levels. Obesity in pregnancy and gestational diabetes are associated with adverse outcomes in infants and children including autism, poor motor skills, lowered IQ, and altered birth weight. Neonatal effects of obesity are confounded by average lower socio-economic status. The already perturbed endocrine balance in overweight or obese persons renders them particularly worthy subjects for clinical epidemiology investigations on the possible effects of endocrine disrupting chemicals. However, inclusion of subjects with obesity requires accounting for potentially confounding effects of the hormonal influences arising from excess adiposity. If subjects with obesity are to be included in clinical epidemiological evaluations related to hormonal effects, the subjects should be classified by body fat percentage rather than by the much less exact measure of body mass index (BMI).

The term oxidative stress was introduced by the National Toxicology Program (NTP) in 1985. It is now invoked as a contributing mechanism to the induction of tumors in chronic rodent cancer bioassays following administration of a chemical agent, especially via inhalation. The term oxidative stress is confusing as there are two different types of oxidative stress. Direct oxidative stress derives from chemical damage to mitochondrial energy-producing structures with concomitantly altered mitochondrial function. Indirect oxidative stress is frequently quantitatively greater than direct oxidative stress in terms of release of activated oxygen or nitrogen species secreted by one or more of 12 potential in situ or recruited inflammatory cell types. Evidence supporting a role for direct oxidative stress in chemical carcinogenesis comes from cell culture studies wherein the cells have been removed from their natural environment and denuded of defense systems, for example, removal of particles by cilia, macrophage engulfment of particles, and suspension and dilution of chemicals or particles in pulmonary surfactant. In contrast, extensive direct evidence from bronchoalveolar lung washes conducted on humans shows elevations in pulmonary macrophage and neutrophil counts, release of intravascular proteins into the extracellular space, and activation of pro-inflammatory cytokines that correlate with observed pulmonary pathology. Higher rates of lung cancer in smokers with chronic obstructive pulmonary disease (COPD) than in smokers at the same cigarette consumption level but without COPD demonstrate a positive contribution by pulmonary inflammation to pulmonary carcinogenesis. Indirect oxidative stress from pulmonary inflammation should be considered before allocating a primary carcinogenic role for direct oxidative stress.