Introduction to the BELLE newsletter: special issue on caloric restriction and hormesis.
Explore the source record for details and available documents.
Adaptation, Physiological↗
Biomedical subjects
E J Calabrese
Publications and source records attributed to E J Calabrese.
Hormesis: a highly generalizable and reproducible phenomenon with important implications for risk assessment.
From a comprehensive search of the literature, the hormesis phenomenon was found to occur over a wide range of chemicals, taxonomic groups, and endpoints. By use of computer searches and extensive cross-referencing, nearly 3000 potentially relevant articles were identified. Evidence of chemical and radiation hormesis was judged to have occurred in approximately 1000 of these by use of a priori criteria. These criteria included study design features (e.g., number of doses, dose range), dose-response relationship, statistical analysis, and reproducibility of results. Numerous biological endpoints were assessed, with growth responses the most prevalent, followed by metabolic effects, reproductive responses, longevity, and cancer. Hormetic responses were generally observed to be of limited magnitude with an average maximum stimulation of 30 to 60 percent over that of the controls. This maximum usually occurred 4- to 5-fold below the NOAEL for a particular endpoint. The present analysis suggests that hormesis is a reproducible and generalizable biological phenomenon and is a fundamental component of many, if not most, dose-response relationships. The relatively infrequent observation of hormesis in the literature is believed to be due primarily to experimental design considerations, especially with respect to the number and range of doses and endpoint selection. Because of regulatory considerations, most toxicologic studies have been carried out at high doses above the low-dose region where the hormesis phenomenon occurs.
Animals↗
The Single Exposure Carcinogen Database: assessing the circumstances under which a single exposure to a carcinogen can cause cancer.
A relational retrieval database has been developed compiling toxicological studies that assess whether a single dose of a chemical or physical agent, without exogenous promotional stimuli, could cause tumor development in animal models. This database allows for an evaluation of these studies over numerous parameters important to tumor outcome, which include type and quality of the studies as well as physical/chemical properties of the agents. An assessment of the database, which currently contains approximately 5500 studies involving about 800 chemicals from 2000 articles, reveals that a single dose of an agent can cause tumors to develop in males and females of numerous animal models in all principal age groups. In addition, the range of the 426 agents causing a positive response is chemically diverse, with representatives from over several dozen chemical classes. The dose caused a tumor endpoint was generally not acutely life threatening and was frequently a low proportion of the LD50 (i.e., less than 1/50 LD50). Positive responses also were reported via multiple routes of exposure, mainly oral, by injection, or dermal. These findings indicate that the phenomenon of single-exposure carcinogenesis is widespread and highly generalizable across chemical class, route, dose range, species, age, and gender. Single-exposure carcinogenesis, a concept long de-emphasized by regulatory agencies, requires a careful and formal consideration, especially as it may pertain to accidental spills, leaks, fires, explosions, and exposure excursions, but not necessarily limited to these.
Age Factors↗
Susceptibility to chlordecone-carbon tetrachloride induced hepatotoxicity and lethality is both age and sex dependent.
The present paper examines the susceptibility to chlordecone (Kepone, CD) and carbon tetrachloride across different ages (35, 45, and 63-days-old) in male and female Sprague-Dawley rats using different lengths of time on a CD diet (10 ppm). The principal findings are that the hepatotoxicity and mortality associated with CD-CCl4 interaction is highly age-dependent for both sexes. There was marked hepatotoxicity occurring in both sexes as they reached 45 days-of-age and females were considerably more susceptible than males to both CD-CCl4-induced hepatotoxicity and lethality. While 63-day-old females are more susceptible to the CD-CCl4 interaction than their male counterparts, the magnitude of the sex difference is diminished from that observed in 45-day-old rats. These findings challenge the hypothesis of Mehendale (1990, Med. Hypotheses 33, 289-299) that chlordecone (CD) pretreatment eliminates the well-established sex difference in CCl4-treated rats. In contrast to the CD-CCl4 findings, the sex difference in CCl4-induced hepatotoxicity was not age-dependent and was consistent over the three ages studied. The findings that CD-CCl4 interaction is highly age-dependent (within the 3 ages tested) but that CCl4-induced hepatotoxicity is not, suggest that the CD-CCl4 interaction acts via a mechanism that does not primarily involve CCl4 potentiation.
Age Factors↗
Evaluation of sex difference in tissue repair following acute carbon tetrachloride toxicity in male and female Sprague-Dawley rats.
Cellular regeneration and tissue repair greatly influence the outcome of acute carbon tetrachloride (CCl4) hepatotoxicity. This study examined the temporal kinetics of cellular regeneration and tissue repair processes in male and female Sprague Dawley (SD) rats following an acute CCl4 exposure (0.8 ml/kg, i.p.). In female rats, hepatic damage peaked at 24 h following the treatment and was approximately 2.5-fold (AST 2.7-fold, ALT 2.3 fold) greater than the damage observed in male rats. The hepatic damage in male rats appeared to peak by 3 h post-exposure and did not significantly change through the 36-h time-point. The activity of cytochrome P 4502E1 was 20% greater in male rats and did not correlate with the magnitude of hepatic damage. Morphometric analysis of cell cycle indices revealed that cellular regeneration was significantly greater in female rats as compared to male rats at 48 h and corresponded proportionally to the extent of liver damage. This study demonstrated that female SD rats respond more severely to acute CCl4 hepatotoxicity than male SD rats and the extent of tissue repair and cellular regeneration was greater in female rats. Furthermore, our results suggest that tissue repair is unlikely to result in accounting for the different responses exhibited by male and female SD rats to CCl4 hepatotoxicity.
Alanine Transaminase↗
Can the concept of hormesis Be generalized to carcinogenesis?
The concept of hormesis (i.e., low-dose stimulation/high-dose inhibition) has been shown to be widely generalizable with respect to chemical class, animal model, gender, and biological end point. The public health implication of this lack of linearity in the low-dose area of the dose-response curve raises the question of whether low doses of carcinogens will reduce cancer risk. Articles relating to the process of carcinogenesis (i.e., initiation, promotion, tumor development, and progression) were obtained from a recently developed chemical hormesis database and evaluated for their evidence of hormesis. Numerous examples in well-designed studies indicate that U- or J-shaped dose-response relationships exist with respect to various biomarkers of carcinogenesis in different animal models of both sexes. Examples of such J-shaped dose-response relationships in each stage of the process of carcinogenesis were selected for detailed toxicological examination. These results have important implications for both the hazard assessment of carcinogens and cancer risk assessment procedures.
Animals↗
A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations.
The development of a comprehensive database of chemical hormetic responses (i.e., U- or inverted U-shaped dose-response relationships) using objective a priori study design, statistical and study replication criteria has recently been reported. An assessment of this database reveals the existence of a wide range of hormetic dose-response relationships including those demonstrating a direct stimulation or an overcompensation response to a disruption of homeostasis. These two broad types of hormetic responses are affected by temporal factors and display unique patterns of dose-range stimulation, magnitude of stimulatory response and relationship of the maximum stimulatory response to the NOAEL. A general classification of U-shaped dose-response relationships is proposed to provide a more organized framework to evaluate the highly distinctive and diverse hormetic responses within the context of establishing underlying biological mechanisms and exploring risk assessment implications.
Animals↗
Hormesis as a default parameter in RfD derivation.
Explore the source record for details and available documents.
Animals↗
Hormesis as a biological hypothesis.
A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer database searches by using various key word descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range), statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biological end points were assessed; growth responses were the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude. The average low-dose maximum stimulation was approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude, with the upper end of the hormetic curve approaching the estimated no observable effect level for the particular end point. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of > 6 doses; with > 3 doses in the hormetic zone. The present analysis suggests that chemical hormesis is a reproducible and relatively common biological phenomenon. A quantitative scheme is presented for future application to the database.
Animals↗
Soil ingestion in adults--results of a second pilot study.
Soil ingestion was evaluated in 10 adults as part of a larger study to evaluate soil ingestion in children. Each adult was followed for 4 weeks in a mass-balance study that was designed to evaluate the detection limit for soil ingestion in a similarly designed, concurrent children's study. After a baseline week, during Weeks 2 through 4, adults received daily soil capsules containing 20, 100, and 500 mg of soil, respectively. A 1-week period separated each study week. Based on the first 3 weeks of observation after subtracting the capsule ingestion amounts, the median, 75th percentile, and 95th percentile soil ingestion estimates were 1, 49, and 331 mg/day, with estimates calculated as the median of the three trace elements Al, Si, and Y. The average estimate of soil ingestion was 10 mg/day (SD = 94 mg/day). These findings augment sparse empirical data on adult soil ingestion, and suggest lower levels of soil ingestion in adults than previous studies.
Adult↗
Soil ingestion estimates for children residing on a superfund site.
Soil ingestion estimates were obtained from a stratified, simple random sample of 64 children aged 1-4 years residing on a superfund site in Montana. The study was conducted during the month of September for 7 consecutive days. The study utilized a mass-balance methodology in which eight naturally occurring soil tracers (Al, Si, Ti, Ce, Nd, La, Y, and Zr) believed to be poorly absorbed by the gastrointestinal tract were employed to provide soil ingestion estimates. Food and fecal samples were analyzed on a daily basis. Soil/dust samples representative of where the children played during the study period were obtained. Very high compliance among the participants was maintained throughout the study. The identical methodology employed in the childrens' study was used in an adult study of tracer recovery in 10 subjects over 28 days of observation to provide validation that soil ingestion over the range of 20 to 500 mg/day could be detected. Soil ingestion was estimated by each soil tracer via traditional methods as well as by an improved approach using five trace elements (Al, Si, Ti, Y, and Zr), called the Best Tracer Method (BTM), which substantially corrects for error due to misalignment of tracer input and output as well as error occurring from ingestion of tracers from nonfood, nonsoil sources, while being insensitive to the particle size of the soil/dust ingested. According to the BTM, the median soil ingestion was less than 1 mg/day while the upper 95% was 160 mg/day. No significant age (1 year vs 2, vs 3) or sex-related differences in soil ingestion were observed. These estimates are lower than estimates observed in another study in Massachusetts during September and October. Significant methodological improvements in this study as compared to previously conducted soil ingestion studies include the selection of a representative sample of children, longer study duration, inclusion of dietary recommendations to reduce food tracer input and variability, use of the BTM, and a stronger adult validation study with respect to number of subjects, and duration and range of possible soil ingestion rates. Despite these methodological improvements, evidence exists that this study displays a net residual negative error, suggesting that the above estimates are below the true soil ingestion. The magnitude of this residual negative error cannot be quantified with the BTM but is likely to not affect the median by more than 40 mg/day, while the impact of such an error on the upper end of the distribution is more uncertain.
Adult↗
A toxicologically based weight-of-evidence methodology for the relative ranking of chemicals of endocrine disruption potential.
A toxicologically based predictive scheme is presented for quantitatively ranking chemical agents with respect to their capacity to ensure endocrine disruption in target species based on short-term bioassays. Criteria providing the predictive framework include: (1) endocrine disruption as a multistage process, (2) phylogenetic considerations, (3) model system, and (4) estrogenic potency. Relative rankings were calculated for 15 environmentally relevant agents reported to have endocrine-disrupting effects. The relative ranking process offers a procedure for assessing the potential of endocrine disruption and for identifying data gaps for specific chemical agents. Although the current scheme is limited to "estrogenic" agents, it is anticipated that future refinements (e.g., incorporation of antiestrogenic potency data) will improve the system.
Animals↗
Striking the balance between the role of animal model and human data in hazard assessment.
Explore the source record for details and available documents.
Animals↗
Soil ingestion: a concern for acute toxicity in children.
Several soil ingestion studies have indicated that some children ingest substantial amounts of soil on given days. Although the EPA has assumed that 95% of children ingest 200 mg soil/day or less for exposure assessment purposes, some children have been observed to ingest up to 25-60 g soil during a single day. In light of the potential for children to ingest such large amounts of soil, an assessment was made of the possibility for soil pica episodes to result in acute intoxication from contaminant concentrations the EPA regards as representing conservative screening values (i.e., EPA soil screening levels and EPA Region III risk-based concentrations for residential soils). For a set of 13 chemicals included in the analysis, contaminant doses resulting from a one-time soil pica episode (5-50 g of soil ingested) were compared with acute dosages shown to produce toxicity in humans in clinical studies or case reports. For four of these chemicals, a soil pica episode was found to result in a contaminant dose approximating or exceeding the acute human lethal dose. For five of the remaining chemicals, the contaminant dose from a soil pica episode was well within the reported dose range in humans for toxicity other than lethality. Because both the exposure episodes and the toxicological response information are derived from observations in humans, these findings are regarded as particularly relevant for human health risk assessment. They suggest that, for some chemicals, ostensibly conservative soil criteria based on chronic exposure using current EPA methodology may not be protective of children during acute soil pica episodes.
Child↗
Expanding the RfD concept to incorporate and optimize beneficial effects while preventing toxic responses from nonessential toxicants.
Increasing evidence that low-level exposure to toxic agents induces beneficial effects indicates the need to examine if and how the current EPA reference dose (RfD) derivation process could take this phenomenon into account. This paper examines conditions that affect how the RfD process could incorporate chemically induced beneficial effects while preventing toxic responses. Incorporation of beneficial responses in the RfD process will be affected by: (i) Size of the dosage range over which the beneficial effects are observed; (ii) proximity of the optimal beneficial response dosage to the NOAEL; and (iii) size of the intraspecies UF. Based on data estimating the distance of the median dosage of the optimal beneficial response from the NOAEL and the recently described lack of independence of the inter- and intraspecies uncertainty factors (UFs), noncarcinogenic toxic substances whose RfDs are based on animal model data are predicted to have their toxic effects prevented and possible beneficial effects optimized in the general population by use of an intraspecies UF of 5. In contrast, current EPA practices of employing a 10-fold UF for intraspecies variation in animal model-based RfD derivation, while also protecting against harmful effects, leads to the general population missing estimated beneficial effects. Such a conclusion has important policy implications since no debate has been directed toward the distribution of population-based pollution-related benefits but only toward the prevention of their harmful effects.
Alcohol Drinking↗
Biochemical individuality: the next generation.
This paper provides an historical assessment of the development of the concepts of pharmaco- and ecogenetics, including their relationship to major developments in the areas of pharmacology, industrial hygiene, and cancer research in animal models as well as the assessment of inborn metabolic disorders. How this information may be used to evaluate the range of human genetic diversity and its relationship to differential responses to environmental toxins is also considered. The paper concludes by providing a brief summary of several specific conditions in which human genetics traits affect susceptibility to toxic substances.
Animals↗
Expanding the reference dose concept to incorporate and optimize beneficial effects while preventing toxic responses from nonessential toxicants.
Increasing evidence that low-level exposure to toxic agents induces beneficial effects indicates the need to examine if and how the current EPA Reference Dose (RfD) derivation process could take this phenomenon into account. This paper examines conditions that affect how the RfD process could incorporate chemically induced beneficial effects while preventing toxic responses. Incorporation of beneficial responses in the RfD process will be affected by: (1) Size of the dosage range over which the beneficial effects are observed; (2) Proximity of the optimal beneficial response dosage to the NOAEL; (3) Size of the intraspecies UF. Based on data estimating the distance of the median dosage of the optimal beneficial response from the NOAEL and the recently described lack of independence of the inter- and intraspecies uncertainty factors (UFs), noncarcinogenic toxic substances whose RfDs are based on animal model data are predicted to have their toxic effects prevented and possible beneficial effects optimized in the general population by use of an intraspecies UF of 5. In contrast, current EPA practices of employing a 10-fold UF for intraspecies variation in animal-model-based RfD derivation while protecting against harmful effects also lead to the general population missing estimated beneficial effects. Such a conclusion has important policy implications since no debate has been directed toward the distribution of population-based pollution-related benefits, but only toward the prevention of their harmful effects.
Animals↗
Methodology to estimate the amount and particle size of soil ingested by children: implications for exposure assessment at waste sites.
Despite considerable efforts to improve the design of soil ingestion studies, substantial variability in daily soil ingestion rates based on different tracer estimates exists in the same subjects. The present study assessed the hypothesis that one of the unexplored causes of this intertracer variation in soil ingestion estimation was related to differences in soil tracer concentration by particle size. The study analyzed the tracer concentration in soil for children in the Anaconda, Montana soil ingestion study for the particle size fraction less than 250 microm [corrected] in diameter. Soil ingestion estimates for these children were recalculated based on the new soil concentration values and compared to previous findings (E. J. Calabrese, E. J. Stanek, P. Pekow, and R. M. Barnes, submitted, 1996) when the soil concentrations were determined for soil particle size diameter of <2 mm. The results indicated that five tracers (Al, Si, Ti, Y, and Zr) did not have their soil concentrations changed by particle size. However, for three tracers (La, Ce, and Nd) the concentration increased by two- to fourfold with the smaller particle size. Recalculation of soil ingestion estimates indicates that the soil ingestion estimates of the five tracers not varying by particle size did not change while those of the remaining three tracers were decreased by approximately 60%. The revised calculations provide a substantial improvement in intertracer estimates of soil ingestion and suggest that the children ingested soil of small particle size. These findings are of significance since they (1) identify an important potential cause of intertracer variability in soil ingestion estimates, (2) establish a new criterion for soil tracer selection, and (3) develop a method for not only providing improved soil ingestion estimates but also determining the particle size of the ingested soil. These findings offer important potential applications for risk assessment practices at contaminated sites since soil ingestion is frequently the dominant route of estimated contaminant exposure in children.
Child↗