Journal of Exposure Science & Environmental Epidemiology, 2020
Background Aggregate exposure, the combined exposures to a single chemical from all pathways, is ... more Background Aggregate exposure, the combined exposures to a single chemical from all pathways, is a critical children’s health issue. Objective The primary objective is to develop a tool to illustrate potential differences in aggregate exposure at various childhood lifestages and the adult lifestage. Methods We developed ExpoKids (an R-based tool) using oral exposure estimates across lifestages generated by US EPA’s Exposure Factors Interactive Resource for Scenarios Tool (ExpoFIRST). Results ExpoKids is applied to illustrate aggregate oral exposure, for ten media, as average daily doses (ADD) and lifetime average daily doses (LADD) in five graphs organized across seven postnatal childhood lifestages and the adult lifestage. This data visualization tool conveys ExpoFIRST findings, from available exposure data, to highlight the relative contributions of media and lifestages to chemical exposure. To evaluate the effectiveness of ExpoKids, three chemical case examples (di[2-ethylhexyl] ...
Caenorhabditis elegans vulval development culminates during exit from the L4-to-adult molt with t... more Caenorhabditis elegans vulval development culminates during exit from the L4-to-adult molt with the formation of an opening through the adult hypodermis and cuticle that is used for egg laying and mating. Vulva formation requires the heterochronic gene lin-29, which triggers hypodermal cell terminal differentiation during the final molt. lin-29 mutants are unable to lay eggs or mate because no vulval opening forms; instead, a protrusion forms at the site of the vulva. We demonstrate through analysis of genetic mosaics that lin-29 is absolutely required in a small subset of lateral hypodermal seam cells, adjacent to the vulva, for wild-type vulva formation and egg laying. However, lin-29 function is not strictly limited to the lateral hypodermis. First, LIN-29 accumulates in many non-hypodermal cells with known roles in vulva formation or egg laying. Second, animals homozygous for one lin-29 allele, ga94, have the vulval defect and cannot lay eggs, despite having a terminally differe...
Mammalian genome : official journal of the International Mammalian Genome Society, Feb 1, 2018
Estimation of susceptibility differences in human health risk assessment (HHRA) has been challeng... more Estimation of susceptibility differences in human health risk assessment (HHRA) has been challenged by a lack of available susceptibility and variability data after exposure to a specific environmental chemical or pharmaceutical. With the increasingly large number of available data sources that contain polymorphism and other genetic data, human genetic variability that informs susceptibility can be better incorporated into HHRA. A recent policy, the 2016 The Frank R. Lautenberg Chemical Safety for the twenty-first Century Act, requires the US Environmental Protection Agency to evaluate new and existing toxic chemicals with explicit consideration of susceptible populations of all types (life stage, exposure, genetic, etc.). We propose using the adverse outcome pathway (AOP) construct to organize, identify, and characterize human genetic susceptibility in HHRA. We explore how publicly available human genetic datasets can be used to gain mechanistic understanding of molecular events an...
FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in N... more FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact ani...
The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a c... more The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties.
TheCaenorhabditis elegansgenelin-29encodes a zinc-finger transcription factor that is required fo... more TheCaenorhabditis elegansgenelin-29encodes a zinc-finger transcription factor that is required for hypodermal cell terminal differentiation and proper vulva morphogenesis. Here we demonstrate thatlin-29is also required in males for productive mating. We show thatlin-29males can perform the early mating behaviors including response to hermaphrodite contact and vulva location, but they do not perform the subsequent steps of vulva attachment via spicule insertion and sperm transfer. Consistent with this observation, we found thatlin-29mutant spicules are on average 43% shorter than wild-type spicules while other male mating structures appear unaltered. Inlin-29mutants, spicule development goes awry after the generation of spicule cells, when spicule morphogenesis occurs in wild-type males. We show that LIN-29 accumulates in many cells of the wild-type male tail, including those that form the spicules. We demonstrate, through analysis of genetic mosaics, that the formation of wild-type-length spicules requireslin-29(+)in the AB.p lineage, the lineage that gives rise to the spicules and other male copulatory structures. Our mosaic analysis also reveals a role forlin-29(+)in the P1 lineage, which mainly produces sex muscles, cells of the somatic gonad, and body wall muscles.
Journal of Toxicology and Environmental Health Part B, Jan 4, 2008
Mode of action (MOA) information is increasingly being applied in human health risk assessment. T... more Mode of action (MOA) information is increasingly being applied in human health risk assessment. The MOA can inform issues such as the relevance of observed effects in laboratory animals to humans, and the variability of response within the human population. Several collaborative groups have developed frameworks for analyzing and utilizing MOA information in human health risk assessment of environmental carcinogens and toxins, including the International Programme on Chemical Safety, International Life Sciences Institute, and U.S. Environmental Protection Agency. With the goal of identifying gaps and opportunities for progress, we critically evaluate several of these MOA frameworks. Despite continued improvement in incorporating biological data in human health risk assessment, several notable challenges remain. These include articulation of the significant role of scientific judgment in establishing an MOA and its relevance to humans. In addition, binary (yes/no) decisions can inappropriately exclude consideration of data that may nonetheless be informative to the overall assessment of risk. Indeed, the frameworks lack a broad consideration of known causes of human disease and the potential for chemical effects to act additively with these as well as endogenous background processes. No integrated analysis of the impact of multiple MOAs over the same dose range, or of varying MOAs at different life stages, is included. Separate consideration of each MOA and outcome limits understanding of how multiple metabolites, modes, and toxicity pathways contribute to the toxicological profile of the chemical. An extension of the analyses across outcomes with common modes is also needed.
Journal of Exposure Science & Environmental Epidemiology, 2020
Background Aggregate exposure, the combined exposures to a single chemical from all pathways, is ... more Background Aggregate exposure, the combined exposures to a single chemical from all pathways, is a critical children’s health issue. Objective The primary objective is to develop a tool to illustrate potential differences in aggregate exposure at various childhood lifestages and the adult lifestage. Methods We developed ExpoKids (an R-based tool) using oral exposure estimates across lifestages generated by US EPA’s Exposure Factors Interactive Resource for Scenarios Tool (ExpoFIRST). Results ExpoKids is applied to illustrate aggregate oral exposure, for ten media, as average daily doses (ADD) and lifetime average daily doses (LADD) in five graphs organized across seven postnatal childhood lifestages and the adult lifestage. This data visualization tool conveys ExpoFIRST findings, from available exposure data, to highlight the relative contributions of media and lifestages to chemical exposure. To evaluate the effectiveness of ExpoKids, three chemical case examples (di[2-ethylhexyl] ...
Caenorhabditis elegans vulval development culminates during exit from the L4-to-adult molt with t... more Caenorhabditis elegans vulval development culminates during exit from the L4-to-adult molt with the formation of an opening through the adult hypodermis and cuticle that is used for egg laying and mating. Vulva formation requires the heterochronic gene lin-29, which triggers hypodermal cell terminal differentiation during the final molt. lin-29 mutants are unable to lay eggs or mate because no vulval opening forms; instead, a protrusion forms at the site of the vulva. We demonstrate through analysis of genetic mosaics that lin-29 is absolutely required in a small subset of lateral hypodermal seam cells, adjacent to the vulva, for wild-type vulva formation and egg laying. However, lin-29 function is not strictly limited to the lateral hypodermis. First, LIN-29 accumulates in many non-hypodermal cells with known roles in vulva formation or egg laying. Second, animals homozygous for one lin-29 allele, ga94, have the vulval defect and cannot lay eggs, despite having a terminally differe...
Mammalian genome : official journal of the International Mammalian Genome Society, Feb 1, 2018
Estimation of susceptibility differences in human health risk assessment (HHRA) has been challeng... more Estimation of susceptibility differences in human health risk assessment (HHRA) has been challenged by a lack of available susceptibility and variability data after exposure to a specific environmental chemical or pharmaceutical. With the increasingly large number of available data sources that contain polymorphism and other genetic data, human genetic variability that informs susceptibility can be better incorporated into HHRA. A recent policy, the 2016 The Frank R. Lautenberg Chemical Safety for the twenty-first Century Act, requires the US Environmental Protection Agency to evaluate new and existing toxic chemicals with explicit consideration of susceptible populations of all types (life stage, exposure, genetic, etc.). We propose using the adverse outcome pathway (AOP) construct to organize, identify, and characterize human genetic susceptibility in HHRA. We explore how publicly available human genetic datasets can be used to gain mechanistic understanding of molecular events an...
FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in N... more FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact ani...
The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a c... more The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties.
TheCaenorhabditis elegansgenelin-29encodes a zinc-finger transcription factor that is required fo... more TheCaenorhabditis elegansgenelin-29encodes a zinc-finger transcription factor that is required for hypodermal cell terminal differentiation and proper vulva morphogenesis. Here we demonstrate thatlin-29is also required in males for productive mating. We show thatlin-29males can perform the early mating behaviors including response to hermaphrodite contact and vulva location, but they do not perform the subsequent steps of vulva attachment via spicule insertion and sperm transfer. Consistent with this observation, we found thatlin-29mutant spicules are on average 43% shorter than wild-type spicules while other male mating structures appear unaltered. Inlin-29mutants, spicule development goes awry after the generation of spicule cells, when spicule morphogenesis occurs in wild-type males. We show that LIN-29 accumulates in many cells of the wild-type male tail, including those that form the spicules. We demonstrate, through analysis of genetic mosaics, that the formation of wild-type-length spicules requireslin-29(+)in the AB.p lineage, the lineage that gives rise to the spicules and other male copulatory structures. Our mosaic analysis also reveals a role forlin-29(+)in the P1 lineage, which mainly produces sex muscles, cells of the somatic gonad, and body wall muscles.
Journal of Toxicology and Environmental Health Part B, Jan 4, 2008
Mode of action (MOA) information is increasingly being applied in human health risk assessment. T... more Mode of action (MOA) information is increasingly being applied in human health risk assessment. The MOA can inform issues such as the relevance of observed effects in laboratory animals to humans, and the variability of response within the human population. Several collaborative groups have developed frameworks for analyzing and utilizing MOA information in human health risk assessment of environmental carcinogens and toxins, including the International Programme on Chemical Safety, International Life Sciences Institute, and U.S. Environmental Protection Agency. With the goal of identifying gaps and opportunities for progress, we critically evaluate several of these MOA frameworks. Despite continued improvement in incorporating biological data in human health risk assessment, several notable challenges remain. These include articulation of the significant role of scientific judgment in establishing an MOA and its relevance to humans. In addition, binary (yes/no) decisions can inappropriately exclude consideration of data that may nonetheless be informative to the overall assessment of risk. Indeed, the frameworks lack a broad consideration of known causes of human disease and the potential for chemical effects to act additively with these as well as endogenous background processes. No integrated analysis of the impact of multiple MOAs over the same dose range, or of varying MOAs at different life stages, is included. Separate consideration of each MOA and outcome limits understanding of how multiple metabolites, modes, and toxicity pathways contribute to the toxicological profile of the chemical. An extension of the analyses across outcomes with common modes is also needed.
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Papers by Susan Euling