Hormesis is a nonlinear dose-response characterized by biological responses at low doses that are opposite to those observed at higher doses. Studies and review articles on hormesis are being published at an increasing rate by researchers from diverse disciplines and debate has emerged over the role hormesis in risk assessment. As a result, a survey was conducted to assess toxicologists and risk assessors knowledge and attitudes about the hormesis dose response. Study goals were to: (1) ascertain attitudes towards hormesis and other dose-response models, (2) identify whether acceptance or rejection of hormesis is based on knowledge of hormesis, predisposing values, or demographic characteristics, and (3) evaluate potential for response bias. The survey consisted of 44 questions pre-tested by 25 toxicologists and risk assessors. The survey was distributed via email to the membership of the Society of Toxicology and the Society for Risk Analysis, 9,500 potential respondents. The overall response rate was 17% (n= 1,463) with a completion rate over 87%. Major findings were that 50% of respondents indicated sufficient data exist to support the view hormesis occurs across a wide range of species and endpoints, 59% indicated evaluating potential benefits due to hormesis should be included in risk assessments, and 65% are in favor of modifying hazard assessment protocols to identify the presence of hormesis. Respondent characteristics such as: years of experience, society membership, education, residence, employment (excluding government and pharmaceutical companies), and political, economic or social views had little influence on opinion. One of the largest positive influences was experience with hormesis based on actual research; 79% of subjects who reported observing hormesis commonly in their studies agreed hormesis is broadly generalizable. The influence of non-response bias was evaluated through several internal and external measures. Despite a lower than hoped for response rate, but because of robust external validity measures, it is concluded that respondents’ opinions are likely a reasonable representation of the societies of which they are members. Because this is a baseline survey, a follow-up survey is in order. Future survey design should separately evaluate the science of dose-response from the regulatory approach to risk assessment.

The developing pancreas has been identified as a potentially sensitive target for oxidative damage caused by environmental toxicant exposure in the developing zebrafish, Danio rerio. The objectives of this study were to 1) investigate the effects of exposure to a common pro-oxidizing toxicant, Mono(2-ethylhexyl) phthalate (MEHP), on pancreatic development, and 2) elucidate redox-sensitive temporal windows of pancreatic organogenesis in the zebrafish. We also investigated the involvement of Nrf2 (Nfe2l2), a transcription factor involved in the oxidative stress response, in toxicant-mediated pancreatic toxicity. In aim one, zebrafish embryos were exposed to 0 or 200 µg/L MEHP beginning at 3 hours post fertilization (hpf) through 168 hpf, and imaged live under a fluorescence microscope to visualize pancreas development from 48-168 hpf. Glutathione (GSH) and cysteine (CyS) redox couples were quantified by HPLC at 72 hpf, and gene expression was investigated at 96 hpf. This study utilized wild type (AB) Tg(ins:GFP), Tg(gcga:GFP) (endocrine islet), and Tg(ptf1a:GFP) (exocrine pancreas) zebrafish strains. We observed that MEHP exposure significantly reduced endocrine islet area and exocrine pancreas length at all timepoints (48, 72, 96, 168 hpf). No significant changes were observed in the redox potential of GSH or Cys, however MEHP exposure significantly altered expression of GSH-related genes (gsr, gstp1), as well as pancreas-specific genes (insa, sst2, ptf1a). These data indicate that the developing pancreas is a sensitive target tissue of embryonic exposure to MEHP. In aim two, we exposed transgenic Tg(ins:GFP) and Tg(gcga:GFP) zebrafish embryos to water, dimethyl sulfoxide (DMSO), N-acetyl cysteine (NAC), sulforophane (SFN), tert-butylhydroperoxide (tBOOH), or tert-butylhydroquinone (tBHQ) at 24, 48, or 72 hours post fertilization (hpf), and assessed endocrine islet morphology at 96 hpf. We found both chemical-, stage-, and cell-type specific effects of redox modulation on the endocrine pancreas. Pro-oxidant exposures resulted in decreased ß-cell cluster area and an increased frequency of islet variants, while antioxidant exposures significantly increased ß-cell cluster area. These effects were most significant at the 48 hpf exposure timepoint. a-cell cluster area was only affected by prooxidant exposure at 48 hpf. These results indicate that ß-cells are uniquely sensitive to oxidative stress, specifically at 48 hpf.

Environmental mercury pollution of the Valley of a Thousand Hills area of KwaZulu-Natal, South Africa, in particular the river system below the Thor Chemicals mercury recycling plant, has been a topic of heated debate for a number of years. Thor Chemicals was established as a mercury recycling plant in the mid-1980' s and it processed mercury waste imported from various countries. A number of factory workers were subsequently exposed to high levels of mercury vapour causing the death of a worker. Upon investigation it was found that in addition to the occupational exposures of workers, mercury waste had been discharged into the river systems of the Valley of a Thousand Hills. During the 1998 South African Parliamentary session, questions were raised regarding the lack of adequate monitoring and research directed at quantifying human health risks in the region. A number of Government departments were accused of apathy and incompetence in adequately addressing the issue. Fish forms an important part of the diet of the local community living in the Valley of a Thousand Hills. Children, in particular, are frequently observed fishing in the rivers, thus placing these individuals at risk should the fish be contaminated with mercury. The aims of this study were: to determine the extent of environmental mercury pollution of the river system downstream from the Thor Chemicals plant, and to quantify the human health risk associated with fish consumption in the region. Samples of streambed sediment, algae, cattle hair, fish and human hair, were obtained from the study area as well as from a control area upstream from the Thor Chemicals plant. These were analysed to determine the concentration of mercury in each sample. Mercury levels in the study group were compared to mercury levels in the control areas.

No description available.

Marbled salamanders (Ambystoma opacum) have individually variable dorsal pigmentation patterns. But it is unclear whether or not dorsal pigmentation is associated with variables such as body size and sex. In this study, we test the hypothesis that the body size variables and sex are important predictors of the coverage of dorsal body white pigmentation in adult marbled salamanders. We evaluate the degree of sexual dimorphism in several body traits, including the dorsal body white pigmentation, using univariate and multivariate methods, and analyze the sex-related difference in pigmentation asymmetry. The General Linear Model (GLM) predicts a significant main effect of sex and a significant interaction between sex and dorsal body area (DBA), influencing the coverage of dorsal body white pigmentation. The interaction effect is greater in males than in females. We show significant sex-related differences in body size and shape. Eight morphometric traits reveal female-biased sexual size dimorphism, while males display a greater coverage of dorsal white pigmentation than females. Prominent female characteristics, compared to males, include a significantly heavier and longer body with a wider trunk, head, neck, shoulder and waist. These sex-specific differences suggest selection for a larger body size in females because of increased maternal reproductive success associated with larger body size. Additionally, females display greater pigmentation asymmetry than males, suggesting a significant sex-related disparity in asymmetric pigmentation. Potential ecological and developmental implications of the observed dimorphism are discussed. To our knowledge, this is the first study demonstrating an association of dorsal white pigmentation with dorsal body area and sex, including a significantly disproportionate pigmentation asymmetry between sexes, in adult marbled salamanders.

Marbled salamanders (Ambystoma opacum) have individually variable dorsal pigmentation patterns. But it is unclear whether or not dorsal pigmentation is associated with variables such as body size and sex. In this study, we test the hypothesis that the body size variables and sex are important predictors of the coverage of dorsal body white pigmentation in adult marbled salamanders. We evaluate the degree of sexual dimorphism in several body traits, including the dorsal body white pigmentation, using univariate and multivariate methods, and analyze the sex-related difference in pigmentation asymmetry. The General Linear Model (GLM) predicts a significant main effect of sex and a significant interaction between sex and dorsal body area (DBA), influencing the coverage of dorsal body white pigmentation. The interaction effect is greater in males than in females. We show significant sex-related differences in body size and shape. Eight morphometric traits reveal female-biased sexual size dimorphism, while males display a greater coverage of dorsal white pigmentation than females. Prominent female characteristics, compared to males, include a significantly heavier and longer body with a wider trunk, head, neck, shoulder and waist. These sex-specific differences suggest selection for a larger body size in females because of increased maternal reproductive success associated with larger body size. Additionally, females display greater pigmentation asymmetry than males, suggesting a significant sex-related disparity in asymmetric pigmentation. Potential ecological and developmental implications of the observed dimorphism are discussed. To our knowledge, this is the first study demonstrating an association of dorsal white pigmentation with dorsal body area and sex, including a significantly disproportionate pigmentation asymmetry between sexes, in adult marbled salamanders.

The prenatal period is a particularly sensitive window of time where development can be impacted by many agents including environmental insults. Exposure to certain chemical, biological, and physical stressors during gestation have been shown to produce adverse health effects in the developing human fetus, as well as throughout an individual’s lifetime. The overall goals of this dissertation were to investigate the impacts of prenatal exposures of environmental stressors on developmental outcomes, including birthweight and neurobehavior, and to explore technologies that can be used to more quickly identify chemicals that may impact the developing fetus. First, we characterize the effects of prenatal air pollution exposure on neurobehavior in childhood. Our work demonstrates the potential impact of prenatal ambient air pollution exposure measured as fine particulate matter (particulate matter ≤ 2.5 μm; PM2.5) exposure on clinically relevant behaviors, specifically thought problems, and suggests that males may be more susceptible to air pollution-induced externalizing behavioral outcomes. In the second aim, we explore critical windows of susceptibility to the effects of various prenatal heat exposure measures on gestational growth. Our work finds that heat index variability is more strongly associated with gestational growth than other heat measures, with disproportionate effects observed in males and those experiencing homelessness during pregnancy. Our third aim compares the utilization and parameterization of New Approach Methodologies for deriving point of departure values that could serve as an alternative to the traditional hazard values derived from animal in vivo studies. Specifically, we examine pesticide chemicals with thyroid-based in vitro endpoints because of the potential impact these chemicals have on in-utero neurodevelopment. We demonstrate that pharmacokinetic model choice and dosing scenario have a substantial impact on predicted values, resulting in estimated values that can be much less restrictive than current values used in regulation. Our work highlights the need for regulators to carefully consider these choices when applying these data to hazard assessments, in order to not underestimate the potential for pesticides to impact maternal thyroid hormones. / 2023-01-24T00:00:00Z

Thesis (Ph.D.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 2000. / Includes bibliographical references. / by Maria Kartalou. / Ph.D.

Thesis (S.M.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 2000. / Includes bibliographical references (leaves 43-47). / Although one million new breast cancer cases arise each year worldwide, therapies to treat the disease are limited. Conventional treatments including the chemotherapeutic agent, Tamoxifen, have had only limited success, often showing uncomfortable side effects. Our group has proposed a new scheme for a rational drug design. This scheme utilizes recent findings on the mechanism of cisplatin, the drug found to cure in excess of 93% of all testicular cancer cases. Cisplatin forms DNA adducts that are toxic. The toxicity of these adducts is enhanced by the recruitment of proteins that bind to the adducts and impede adduct repair. This thesis was an attempt to duplicate this "repair shielding" mechanism with another cytotoxin. Specifically, this toxin will be programmed to kill breast cancer cells. Breast cancer cells often overexpress the estrogen receptor protein. By synthesizing a drug that not only binds and damages the DNA but also binds the abundant proteins in the cells, thereby blocking the damaged site from DNA repair proteins, a selective treatment of cancer cells can be achieved. In this study, the human estrogen receptor (hER) and the ligand binding domain of the hER genes were cloned into baculovirus expression vectors, establishing a system where a large quantity of the proteins can be expressed. The proteins expressed in insect cells were purified in one step, using the FLAG-epitope, yielding homogeneous proteins. The proteins were tested for binding to p-estradiol and were confirmed to be functional in ligand binding. They were also tested for their ability to bind the novel drugs synthesized to bind both the protein and the DNA. It was found that the ligand binding domain of the hER was capable of binding the drugs adducted to the DNA. In an effort to elucidate the mechanism of the protein-drug-DNA complex formation, an association experiment was carried out, which showed that the drug more readily bound to the protein than to DNA. However, a significant amount of the drug-protein complex still bound the DNA, if the ratio of the protein to the drug did not exceed 1.5. / by Annie S. Lee. / S.M.

Thesis (S.M.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 1999. / Includes bibliographical references (leaves 9-10). / by Jim Hansen. / S.M.