Evaluation of analytical similarity between trastuzumab biosimilar CT-P6 and reference product using statistical analyses

The evaluation of analytical similarity has been a challenging issue for the biosimilar industry because the number of lots for reference and biosimilar products available at the time of development are limited, whilst measurable quality attributes of target molecule are numerous, which can lead to potential bias or false negative/positive conclusions regarding biosimilarity. Therefore, appropriate statistical analyses are highly desirable to achieve a high level of confidence in the similarity evaluation. A recent guideline for the risk-based statistical approaches recommended by the US Food and Drug Administration provides useful tools to systematically evaluate analytical similarity of biosimilar products compared with reference products. Here, we evaluated analytical similarity of CT-P6, a biosimilar product of trastuzumab, with the reference products (EU-Herceptin® or US-Herceptin®) following these statistical approaches. Various quality attributes of trastuzumab were first ranked based on the clinical impact of each attribute and subsequently adjusted to one of three tiers (Tier 1, Tier 2 and Tier 3) considering the characteristics of the assay, the level of attribute present and the feasibility of statistical analysis. Two biological activities with highest potential clinical impact were evaluated by an equivalent test (Tier 1), and other bioactivities and structural/physicochemical properties relevant to the clinical impact were evaluated by a quality range approach (Tier 2). The attributes with low risk ranking or qualitative assay were evaluated by visual comparison (Tier 3). Analytical similarity assessment analyzed by the three tiers clearly demonstrated that CT-P6 exhibits highly similar structural and physicochemical properties, as well as functional activities, compared with the reference products. There were small differences observed in a few quality attributes between CT-P6 and the reference products, but the differences were very minor, and unlikely to impact on clinical outcome. The recently reported equivalent clinical efficacy of CT-P6 with the reference product further supports that CT-P6 is highly similar compared with the reference product in the view of totality-of-evidence.     

Improving the accounting of field emissions in the carbon footprint of agricultural products: a comparison of default IPCC methods with readily available medium-effort modeling approaches

Purpose

The estimations of greenhouse gas (GHG) field emissions from fertilization and soil carbon changes are challenges associated with calculating the carbon footprint (CFP) of agricultural products. At the regional level, the IPCC Guidelines for National Greenhouse Gas Inventories (2006a) Tier 1 approach, based on default emission factors, insufficiently accounts for emission variability resulting from pedo-climatic conditions or management practices. However, Tier 2 and 3 approaches are usually considered too complex to be practicable. In this paper, we discuss different readily available medium-effort methods to improve the accuracy of GHG emission estimates.

Methods

We present four case studies—two wheat crops in Germany and two peach orchards in Italy—to test the performance of Tier 1, 2, and 3 methodologies and compare the estimated results with available field measurements. The methodologies selected at Tier 2 and Tier 3 level are characterized by simple implementation and data collection, for which only a medium level of effort for stakeholders is required. The Tier 2 method consists of calculating direct and indirect N₂O, emissions from fertilization with a multivariate empirical model which accounts for pedo-climatic and crop management conditions. The Tier 3 method entails simulation of soil carbon stock change using the Rothamsted carbon model.

Results and discussion

Relevant differences were found among the tested methodologies: in all case studies, the Tier 1 approach exceeded the Tier 2 estimations for fertilizer-induced emissions (up to +50 %) and the measurements. Using this higher Tier approach reduced the estimated CFP calculation of annual crops by 4 and 21 % and that of the perennial crop by 7 %. Removals related to positive soil carbon change calculated using the Tier 1 approach also exceeded the Tier 3 calculations for the studied annual crops (up to +90 %) but considerably underrated the Tier 3 estimations and measurements for perennial crops (?75 %). In this case, the impact of the selected Tier method on the final CFP results was even more relevant: an increase of 194 and 88 % for the studied annual crops and a decrease of 67 % for the perennial crop case study.

Conclusions

The use of higher Tiers for the estimation of land-based emissions is strongly recommended to improve the accuracy of the CFP results. The suggested medium-effort methods tested in this study represent a good compromise between complexity reduction and accuracy improvement and can be considered reliable for the assessment of GHG mitigation potentials.

     

An Application of Delaware's Risk-Based Corrective Action Program: To a Site with MTBE Contamination

MTBE is a gasoline additive addressed in Delaware's Risk-Based Corrective Action Program. Due to inconclusive toxicological data, MTBE is difficult to address in a risk-based fashion pertaining to actual cancer risk. MTBE action levels in Delaware's Risk-Based Corrective Action Program (DERBCAP) are based on the low end of the aesthetic range of the contaminant (10 ppb), not a health-based number. Addressing MTBE in this manner can make it very amenable to risk-based decision making. When MTBE concentrations exceed Tier 1 RBSL values, the site must be remediated to those values or modeled in Tier 2 to calculate Site Specific Target Levels (SSTLs) and demonstrate a stable and shrinking plume. A case study is provided to evaluate the applicability of MTBE in DERBCAP at a site where several shallow, private supply wells were contaminated with MTBE following a gasoline release several hundred feet up-gradient. Following well replacement and site characterization, Tier 2 modeling was performed to establish clean-up goals (RBCA Toolkit). By using initial concentrations at the POC wells and forward calculating concentrations down-gradient, clean up goals were established for the 180 and 230 m POCs at 500 and 1100 ppb, respectively. These clean up goals will be protective of the 10 ppb maximum exposure limit (MEL) established at the down-gradient point of exposure (POE). Modflow (WHI) and MT3D (Zheng 1990) were used to determine if the pump and treat remediation schedule set forth by the consultant was sufficient to remediate to the calculated clean up levels. Transient simulations showed that pumping from wells on the leading and trailing edge of the plume “core” for 1 week each month for 2 years resulted in a drop in POE and source concentrations of 40 to 60%. Although the drop is significant, the down-gradient POE would still be in jeopardy of exceeding the MEL. This suggests that additional and/or more frequent remediation may be necessary.     

Tier-1 assays for assessing the toxicity of insecticidal proteins produced by genetically engineered plants to non-target arthropods

In assessing an insect-resistant genetically engineered （IRGE） crop before its commercialization, researchers normally use so-called ＂Tier-1 assays＂ as the initial step to determine the effects of the crop on non-target organisms. In these tests, the insecticidal proteins （IPs） produced by the IRGEs are added to the diets of test organisms in the laboratory. Test organisms in such assays can be directly exposed to much higher concentrations of the test IPs than they would encounter in the field. The results of Tier-1 assays are thus more conservative than those generated in studies in which the organisms are exposed to the IPs by feeding on IRGE plant tissue or in the case of predators or parasites, by feeding on invertebrate prey or hosts that have fed on IRGE plant tissue. In this report, we consider three important factors that must be considered in Tier-1 assays： （i） methods for delivery of the IP to the test organisms; （ii） the need for and selection of compounds used as positive controls; and （iii） methods for monitoring the concentration, stability and bioactivity of the IP during the assay. We also analyze the existing data from Tier-1 assays regarding the toxicity of Bt Cry proteins to non-target arthropod species. The data indicate that the widely used Bt proteins have no direct toxicity to non-target organisms     

MENTAL HEALTH—A Discussion of Various Program Approaches Used in California and the Basic Assumptions Involved

The nation''s Number One health problem, mental illness, compels careful reevaluation of past and current methods of attack. It also invites consideration of the ways and means of integrating preventive measures that emphasize the conservation of mental health with prophylactic efforts that stress the avoidance of mental illnesses.A review of the development of both local and statewide mental health programs in California reveals that three fundamentally different approaches have been used: (1) The traditional approach which confines itself to the protection of society from the “insane” by the state, and to the treatment of those who are not legally insane through “private enterprise”; (2) the public health approach which seeks to minimize the causes and/or spread of selected types of psychiatric disorder regarded as mass phenomena; and (3) the sociological approach which stresses the importance of social factors both in the causation and in the rehabilitation of those mental conditions that are considered to be symptomatic of a “sick” society.An approach that combines the theoretical and practical implications of all three viewpoints offers some new solutions to the problems of (1) fitting mental health programs to populations; (2) financing; and (3) balancing preventive and clinical services.Mental illness is not a single disease-entity but a long list of distinctly different conditions. The causes and manifestations are multiple. Biological, psychological and social components in either mental health or mental illness cannot be dissociated in any attempt to understand and deal with so wide a range of illnesses and states of comparative health. Therefore, many professions and multiple public and private agencies are involved in planning, developing and administering a mental health program.     

Health-Based Criteria for Sediment Disposal Options: A Case Study of the Port of New York/New Jersey

Approximately 4 million cubic yards of sediment are dredged annually from the Port of New York and New Jersey in order to maintain navigable channels. In many cases, the sediments contain elevated levels of numerous contaminants. The New York District of the U.S. Army Corps of Engineers and U.S. Environmental Protection Agency Region II employ a framework of sediment quality evaluation to determine whether contaminated sediments are suitable for open ocean disposal (i.e., do not pose a health risk from bioaccumulation in human food chain) or whether more extensive and costly disposal methods are required. The degree to which chemicals can bioaccumulate from sediments into benthic invertebrates is a key determinant in the permitting decision. The maximally “acceptable” levels of bioaccumulation (bioaccumulation criteria) have been developed over a period of several years, using a variety of different methods. We reviewed the technical bases of these criteria and found that, while some values can be considered “risk-based,” others are based on historical background concentrations, Food and Drug Administration Action Levels, limits of detection, and other non-“risk-based” methodologies. Hence, the degree of uncertainty and health protection (or lack thereof) in the criteria varies considerably among the chemicals. We also reviewed the outcomes of several permit applications and found that the bioaccumulation criteria were not applied consistently. We propose the following refinements to the decision-making process: (1) bioaccumulation screening values based only upon risk-based criteria, using a single method that is applied for all chemicals; (2) increased consistency in decision-making and considerations of site-specific information where appropriate; and (3) assured availability of testing results for review and analysis by interested parties.     

Epistatic interactions among herbicide resistances in Arabidopsis thaliana: the fitness cost of multiresistance

The type of interactions among deleterious mutations is considered to be crucial in numerous areas of evolutionary biology, including the evolution of sex and recombination, the evolution of ploidy, the evolution of selfing, and the conservation of small populations. Because the herbicide resistance genes could be viewed as slightly deleterious mutations in the absence of the pesticide selection pressure, the epistatic interactions among three herbicide resistance genes (acetolactate synthase CSR, cellulose synthase IXR1, and auxin-induced AXR1 target genes) were estimated in both the homozygous and the heterozygous states, giving 27 genotype combinations in the model plant Arabidopsis thaliana. By analyzing eight quantitative traits in a segregating population for the three herbicide resistances in the absence of herbicide, we found that most interactions in both the homozygous and the heterozygous states were best explained by multiplicative effects (each additional resistance gene causes a comparable reduction in fitness) rather than by synergistic effects (each additional resistance gene causes a disproportionate fitness reduction). Dominance coefficients of the herbicide resistance cost ranged from partial dominance to underdominance, with a mean dominance coefficient of 0.07. It was suggested that the csr1-1, ixr1-2, and axr1-3 resistance alleles are nearly fully recessive for the fitness cost. More interestingly, the dominance of a specific resistance gene in the absence of herbicide varied according to, first, the presence of the other resistance genes and, second, the quantitative trait analyzed. These results and their implications for multiresistance evolution are discussed in relation to the maintenance of polymorphism at resistance loci in a heterogeneous environment.     

Public education improves farmers knowledge and management of invasive alien species

Research into the human dimensions of invasive alien species (IAS) management has received great attention to date. However, little is known about how public education influences stakeholders knowledge and management of IAS. Using key informant interviews and household questionnaires, we explored the role of public education in farmers knowledge and management of invasive Mikania micrantha in the China-Myanmar Border Region (China). We found ten common educational approaches that farmers were familiar with and/or adopted, and a high level of knowledge and management among farmers. We also found that public educational approaches helped to improve farmers knowledge and management, with some differences due to socio-demographic factors. We conclude that promotional materials and training workshops work better than personal experience, and that training workshops perform best. These results suggest that improving the design and implementation of public education could contribute to effective communication among stakeholders and long-term management of IAS. Our findings provide important insights for adopting public education programs in IAS management.

     

Navigating the mtDNA road map out of the morphological maze: interpreting morphological variation in the diverse Monomorium rothsteini (Forel) complex (Hymenoptera: Formicidae)

Monomorium is a large and diverse ant genus with speciose radiations in both the Afrotropical and Australian regions. According to the most recent taxonomic revision, many Australian species are characterised by very broad distributions and variable morphology, which suggests that some species may be unrecognised species complexes. With a continent‐wide distribution and diverse yet overlapping morphology, M. rothsteini (Forel) is representative of the greater challenge that exists in Australian Monomorium systematics. Here we investigate species boundaries in M. rothsteini using a molecular phylogenetic framework to interpret the complex overlap of nine morphological characters (with 31 states) and examine biogeographic relationships among the lineages. Bayesian inference resolved 38 mtDNA lineages that were morphologically separable, at least from their sister lineage. Although the morphological characters were intermixed across the phylogeny, instances of inseparable morphology among sister clades was rare. Seventeen lineages exhibited complete morphological overlap with one or more other lineages and could not be separated by Principal Component Analysis based on 12 morphometric variables. Two‐thirds of all lineages occurred sympatrically with one or more both genetically and morphologically divergent lineages. The two nuclear markers EF1αF2 and wingless were used to generate haplotype networks which were characterised by a star‐like pattern indicative of a rapid and recent radiation. Several haplotypes for both nuclear gene regions were shared among individuals occurring in separate mtDNA clades which we were also unable to distinguish morphologically or that were occurring in sympatry, indicating possible introgression in both the mtDNA and nuclear genomes. Clear biogeographic affinities among samples within a lineage were detected but there was no overall pattern in the biogeographic relationships among the lineages. We conclude that M. rothsteini is a large species complex that has undergone a complex evolutionary history following aridification of the Australian continent, and discuss the implications of this conclusion for the systematics of Australian Monomorium more generally.     

In situ measurement of leaf chlorophyll concentration: analysis of the optical/absolute relationship

In situ optical meters are widely used to estimate leaf chlorophyll concentration, but non‐uniform chlorophyll distribution causes optical measurements to vary widely among species for the same chlorophyll concentration. Over 30 studies have sought to quantify the in situ/in vitro (optical/absolute) relationship, but neither chlorophyll extraction nor measurement techniques for in vitro analysis have been consistent among studies. Here we: (1) review standard procedures for measurement of chlorophyll; (2) estimate the error associated with non‐standard procedures; and (3) implement the most accurate methods to provide equations for conversion of optical to absolute chlorophyll for 22 species grown in multiple environments. Tests of five Minolta (model SPAD‐502) and 25 Opti‐Sciences (model CCM‐200) meters, manufactured from 1992 to 2013, indicate that differences among replicate models are less than 5%. We thus developed equations for converting between units from these meter types. There was no significant effect of environment on the optical/absolute chlorophyll relationship. We derive the theoretical relationship between optical transmission ratios and absolute chlorophyll concentration and show how non‐uniform distribution among species causes a variable, non‐linear response. These results link in situ optical measurements with in vitro chlorophyll concentration and provide insight to strategies for radiation capture among diverse species.     

Approaches to Ecological Risk Characterization and Management: Selecting the Right Tools for the Job

Chemical-specific hazard quotient (HQ) risk characterization in ecological risk assessment (ERA) can be a value-added tool for risk management decision-making at chemical release sites, when applied appropriately. However, there is little consensus regarding how HQ results can be used for risk management decision-making at the population, community, and ecosystem levels. Furthermore, stakeholders are reluctant to consider alternatives to HQ results for risk management decisions. Chemical-specific HQs risk characterization should be viewed as only one of several approaches (i.e., tools) for addressing ecological issues; and in many situations, other quantitative and qualitative approaches will likely result in superior risk management decisions. The purpose of this paper is to address fundamental issues and limitations associated with chemical-specific HQ risk characterization in ERA, to identify when it may be appropriate, to explore alternatives that are currently available, and to identify areas that could be developed for the future. Several alternatives (i.e., compensatory restoration, performance-based ecological monitoring, ecological significance criteria, net environmental benefit analysis), including their limitations, that can supplement, augment, or substitute for HQs in ERA are presented. In addition, areas of research (i.e., wildlife habitat assessment/landscape ecology/population biology, and field validated risk-based screening levels) that could yield new tools are discussed.     

The use of biomarkers in biomonitoring: a 2-tier approach assessing the level of pollutant-induced stress syndrome in sentinel organisms

The paper outlines a 2-tier approach for wide-scale biomonitoring programmes. To obtain a high level of standardization, we suggest the use of caged organisms (mussels or fish). An "early warning", highly sensitive, low-cost biomarker is employed in tier 1 (i.e. lysosomal membrane stability (LMS) and survival rate, a marker for highly polluted sites). Tier 2 is used only for animals sampled at sites in which LMS changes are evident and there is no mortality, with a complete battery of biomarkers assessing the levels of pollutant-induced stress syndrome. Possible approaches for integrating biomarker data in a synthetic index are discussed, along with our proposal to use a recently developed Expert System. The latter system allows a correct selection of biomarkers at different levels of biological organisation (molecular/cellular/tissue/organism) taking into account trends in pollutant-induced biomarker changes (increasing, decreasing, bell-shape). A selection of biomarkers of stress, genotoxicity and exposure usually employed in biomonitoring programmes is presented, together with a brief overview of new biomolecular approaches.     

The macrophage-specific membrane protein Nramp controlling natural resistance to infections in mice has homologues expressed in the root system of plants

In mice, natural resistance or susceptibility to infection with Mycobacteria, Salmonella, and Leishmania is controlled by a gene named Bcg. Bcg regulates the capacity of macrophages to limit intracellular replication of the ingested parasites, and is believed to regulate a key bactericidal mechanism of this cell. Recently, we have cloned the Bcg gene and shown that it encodes a novel macrophage-specific membrane protein designated Nramp. A routine search of the public databases for sequences homologous to Nramp identified 3 expressed sequence tags (EST) that show strong similarities to the mammalian protein.We report the identification and cloning of a full-length cDNA clone corresponding to a plant homologue (OsNramp1) of mammalian Nramp. Predicted amino acid sequence analysis of the plant protein indicates a remarkable degree of similarity (60% homology) with its mammalian counterpart, including identical number, position, and composition of transmembrane domains, glycosylation signals, and consensus transport motif, suggesting an identical overall secondary structure and membrane organization for the two proteins. This high degree of structural similarity indicates that the two proteins may be functionally related, possibly through a common mechanism of transport. RNA hybridization studies and RT-PCR analyses indicate that OsNramp1 mRNA is expressed primarily in roots and only at very low levels in leaves/stem. DNA hybridization studies indicate that OsNramp1 is not a single gene, but rather forms part of a novel gene family which has several members in all plants tested including cereals such as rice, wheat, and corn, and also in common weed species. The striking degree of conservation between the macrophage-specific mammalian Nramp and its OsNramp1 plant homologue is discussed with respect to possible implications in the metabolism of nitrate in both organisms.     

Applying a Watershed-Level,Risk-Based Approach to Addressing Legacy Mercury Contamination in the South River,Virginia: Planning and Problem Formulation

In 2001, the DuPont Company and various Virginia regulatory agencies (Virginia) established the South River Science Team (SRST) as a multi-stakeholder and collaborative program to address legacy Hg contamination of the South River, Virginia. Specifically, the SRST began to apply a watershed-level risk-based assessment process to evaluate the potential impact of a former DuPont facility adjacent to the South River. Mercury had been found in facility soils in 1976 spawning numerous chemical and biological studies. However, prior to 1999, with the exception of a structured, long-term fish monitoring plan developed by Virginia, these studies were conducted by diverse, independent organizations resulting in limited scientific oversight and implementation, or interaction with the public. This article focuses on some key findings (e.g., defining/refining the issues, setting up the team, the role of the different stakeholders in making the process work) from the problem formulation and planning phase of this multi-stakeholder effort. The SRST effort draws heavily on the concepts of problem formulation (PF) and planning (as described by the U.S. Environmental Protection Agency) to guide the overall risk-based approach. PF is one of the most important steps in the process and, if done correctly can lead to a well-conceived and implemented assessment.     

Screening of Ole e 1 polymorphism among olive cultivars by peptide mapping and N‐glycopeptide analysis

In the present paper, we have used 2‐DE coupled to MS analysis to examine the molecular variability of the Ole e 1 allergen in three olive cultivars (cvs). Our results confirmed that the predicted polymorphism of Ole e 1 at cDNA level is extended to the expressed protein. The profiles of both the Ole e 1 peptides and the N‐glycan variants significantly changed among cvs. We observed that Picual and Arbequina cvs presented the highest and lowest degree of Ole e 1 polymorphism, respectively. Some of these peptides and N‐glycans were distributed in a cv‐specific manner. The putative implications of this molecular polymorphism in the development of the allergy symptoms are discussed.     

Distribution of Competition Potential Between Native Ungulates and Free-Roaming Equids on Western Rangelands

Free-roaming equids (i.e., feral horses [Equus caballus] and burros [Equus asinus]) are widely distributed and locally abundant across the rangelands of the western United States. The 1971 Wild Free Roaming Horse and Burro Act (WFRHBA) gave the Bureau of Land Management (BLM) and United States Forest Service (USFS) the legal authority to manage these animals on designated public lands. To fulfill this responsibility, federal agencies established an Appropriate Management Level (AML), defined as the number of horses or burros that can be sustained on a given management unit under prevailing environmental conditions and land uses. Although the WFRHBA specifies that feral equids must be managed in ecological balance with other land uses, including conservation of native wildlife, population control measures such as gathers, contraception, and adoptions have failed to keep pace with intrinsic growth rates. Over 80% of federally managed herds currently exceed prescribed population levels, making the potential for competition between native ungulates and feral equids a growing concern among state wildlife agencies. Mule deer (Odocoileus hemionus), pronghorn (Antilocapra americana), elk (Cervus canadensis), and bighorn sheep (Ovis canadensis) are of ecological and economic value to the states where they occur, and all exhibit some degree of distributional, habitat, or dietary overlap with horses or burros. Notwithstanding the scale of the problem, to date there have been no range-wide assessments of competition potential among native and feral ungulates for space, forage, or water. To address this need, we compiled demographic, jurisdictional, and species occurrence data collected from 2010–2019 by federal and state agencies. We used these data to map the distributions of 4 native ungulate species across federal equid management units (FEMUS) in 10 western states (n = 174). We then made within-state rankings of the 50 units that were ≥2 times over AML and encompassed ≥3 native ungulates. Collectively, FEMUs covered approximately 225,000 km², representing 18% of all BLM and USFS lands in affected states. Each FEMU supported ≥1 native ungulate and 14% contained all 4. The degree of overlap between native and feral species varied by state, ranging from <1% for mule deer in Montana, to 40% for bighorn sheep in Nevada. Oregon had the largest proportion of units that supported all 4 native ungulates (58%), whereas Montana and New Mexico had the fewest equids, but all populations were over target densities. Despite the perception that the problem of equid abundance is limited to the Great Basin states, high intrinsic growth rates and social constraints on management practices suggest all affected states should monitor range conditions and native ungulate demography in areas where forage and water resources are limited and expanding equid populations are a concern. © 2021 The Wildlife Society.     

Spatial population genomics of the brown rat (Rattus norvegicus) in New York City

Human commensal species such as rodent pests are often widely distributed across cities and threaten both infrastructure and public health. Spatially explicit population genomic methods provide insights into movements for cryptic pests that drive evolutionary connectivity across multiple spatial scales. We examined spatial patterns of neutral genomewide variation in brown rats (Rattus norvegicus) across Manhattan, New York City (NYC), using 262 samples and 61,401 SNPs to understand (i) relatedness among nearby individuals and the extent of spatial genetic structure in a discrete urban landscape; (ii) the geographic origin of NYC rats, using a large, previously published data set of global rat genotypes; and (iii) heterogeneity in gene flow across the city, particularly deviations from isolation by distance. We found that rats separated by ≤200 m exhibit strong spatial autocorrelation (r = .3, p = .001) and the effects of localized genetic drift extend to a range of 1,400 m. Across Manhattan, rats exhibited a homogeneous population origin from rats that likely invaded from Great Britain. While traditional approaches identified a single evolutionary cluster with clinal structure across Manhattan, recently developed methods (e.g., fineSTRUCTURE, sPCA, EEMS) provided evidence of reduced dispersal across the island's less residential Midtown region resulting in fine‐scale genetic structuring (F_ST = 0.01) and two evolutionary clusters (Uptown and Downtown Manhattan). Thus, while some urban populations of human commensals may appear to be continuously distributed, landscape heterogeneity within cities can drive differences in habitat quality and dispersal, with implications for the spatial distribution of genomic variation, population management and the study of widely distributed pests.     

Comparison of Approaches for Developing Distributions for Carcinogenic Slope Factors

In recent years, risk assessors have increasingly been moving away from deterministic risk assessment approaches and are applying probabilistic approaches that incorporate distributions of possible values for each input parameter. This paper reviews several approaches that are being used or that could potentially be used to develop distributions for carcinogenic slope factors (CSFs). Based on the primary tool or framework that is applied, these approaches have been divided into the following three categories: the statistical framework, the decision analysis framework, and the biological framework. Work that has been done on each approach is summarized, and the aspects of variability and uncertainty that are incorporated into each approach are examined. The implications of the resulting distributional information for calculating risk estimates or risk-based concentrations is explored. The approaches differ in their stage of development, the degree to which they diverge from the U.S. Environmental Protection Agency's (EPA) current practice in establishing CSF values, their flexibility to accommodate varying data sets or theories of carcinogenicity, and their complexity of application. In some cases, wide ranges of potential potency estimates are indicated by these approaches. Such findings suggest widely divergent risk assessment implications and the need for additional evaluation of the goals of developing CSF distributions for use in risk assessment applications and the types of information that should be reflected in such distributions. Some combination of the features offered by these approaches may best support risk assessment and risk management decisions.     

Drinking during downturn: New evidence from the housing market fluctuations in the United States during the Great Recession

We investigate how the decline in home prices over the Great Recession in the U.S. impacted drinking behavior. We match data on actual and shadow home prices (from Zillow Research) to individuals’ drinking behavior from the Behavioral Risk Factor Surveillance System (BRFSS) by county of residence and year/month of the interview. We improve upon the existing literature by using new measures of exogenous macroeconomic shocks captured by fluctuations in home prices and finding heterogeneous impacts of the downturn based on homeownership. We find that decline in home prices is commonly associated with increases in alcohol consumption, both on extensive and intensive margins. Additionally, we find that the effects are more consistent among homeowners compared to renters. Given that alcohol consumption is one of the leading causes of death in the U.S. and that the COVID-19 pandemic has triggered an economic crisis in many societies, the results have important public health implications.