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C A Kimmel

Publications and source records attributed to C A Kimmel.

At least 19 recordsLinked to original sources
PubMed2002

Response-surface analysis of exposure-duration relationships: the effects of hyperthermia on embryonic development of the rat in vitro.

In developing exposure standards, an assumption is often made in the case of less-than-lifetime exposures that the probability of response depends on the cumulative exposure, i.e., the product of exposure concentration and duration. Over the last two decades, the general applicability of this assumption, referred to as Haber's Law, has begun to be questioned. This study examined the interaction of exposure concentration and duration on embryonic development during a portion of organogenesis. Embryos were exposed in whole embryo culture to various temperature-duration combinations and evaluated for alterations in development 24 h later. The specific purpose of the study was to assess whether the developmental responses followed Haber's Law, or whether an additional component of exposure was needed to model the relationship. The current study demonstrated that the response of the developing embryo to hyperthermia, with rare exception, was dependent on an additional component of exposure beyond the cumulative exposure. For the vast majority of the parameters measured in this study, the probability of an effect was greater at higher temperatures for short durations than at lower temperatures for long durations, given the same cumulative exposure. Thus, Haber's Law did not adequately describe the results of our study.

Algorithms↗
PubMed2001

Developmental stage sensitivity and mode of action information for androgen agonists and antagonists.

The response from exposure to a toxic agent during development may vary depending on the dose, time of exposure and the mode of action. The mode of action and developmental stage sensitivity are established only for a limited number of chemical classes. Some aspects of developmental stage sensitivity that appear to affect the response to androgen agonists and antagonists are the levels and distribution of endogenous androgens and the androgen receptor at particular times during development. This information is summarized and discussed as it relates to two critical windows of development: the period of male reproductive tract differentiation, and the peripubertal period when male sexual maturation occurs. Developmental stage sensitivity and mode of action data for the androgen antagonist vinclozolin are reviewed. Vinclozolin acts by binding to and activating the androgen receptor and affects a number of endpoints of reproductive tract differentiation as well as pubertal maturation. Approaches to incorporating mode of action, developmental stage sensitivity, and dose/potency information into risk assessment, as well as the additional data needed for using mode of action information, both qualitatively and quantitatively, in risk assessment are discussed. These issues are also considered in the context of combining the risks of exposure to two or more chemicals with similar modes of action.

Aging↗
PubMed2001

Recent developments in regulatory requirements for developmental toxicology.

A number of legislative and regulatory changes have occurred over the past 5 years to prompt the re-evaluation of the regulatory requirements for developmental toxicity testing and use of the data for risk assessment. In particular, passage of the 1996 Food Quality Protection Act (FQPA) in the United States required the USEPA to evaluate children's health risks in a more rigorous fashion, and to apply an additional 10-fold safety factor if data were inadequate or children appeared to be more sensitive than adults. A review of the testing protocols required by USEPA led to extension of the dosing period to term in the prenatal developmental toxicity study and the addition of endpoints to the 2-generation reproduction study protocol as indicators of possible neurologic, reproductive, or immune alterations. Revised testing guidelines for pesticides and toxic substances were published by USEPA in 1998, including a developmental neurotoxicity testing protocol. Further review for FQPA implementation resulted in the proposal for a core set of required toxicology studies, including routine developmental neurotoxicity, adult neurotoxicity, and adult immunotoxicity studies. In addition, development of new testing guidelines in several areas was recommended, these guidelines to be used in conjunction with or as follow-up when indicated from standard testing: developmental immunotoxicity, carcinogenesis, specialized neurotoxicity studies, endocrine disruptor studies, pharmacokinetics, and direct dosing of neonates. The impact of these efforts on the policies for toxicity testing of pesticides are discussed, and these issues are currently being reviewed on a broader scale, in particular, by evaluating the adequacy of the methods used for reference values (e.g. chronic RfD, RfC). Three major areas of focus for this review include life stages evaluated, endpoints assessed, and the duration of exposure used in various studies. A major focus of these efforts is to ensure that children's health risks are being adequately addressed in the risk assessment process.

Animals↗
PubMed2001

Harmonization of cancer and noncancer risk assessment: proceedings of a consensus-building workshop.

Significant advancements have been made toward the use of all relevant scientific information in health risk assessments. This principle has been set forth in risk-assessment guidance documents of international agencies including those of the World Health Organization's International Programme on Chemical Safety, the U.S. Environmental Protection Agency, and Health Canada. Improving the scientific basis of risk assessment is a leading strategic goal of the Society of Toxicology. In recent years, there has been a plethora of mechanistic research on modes of chemical toxicity that establishes mechanistic links between noncancer responses to toxic agents and subsequent overt manifestations of toxicity such as cancer. The research suggests that differences in approaches to assessing risk of cancer and noncancer toxicity need to be resolved and a common broad paradigm for dose-response assessments developed for all toxicity endpoints. In November 1999, a workshop entitled "Harmonization of Cancer and Noncancer Risk Assessment" was held to discuss the most critical issues involved in developing a more consistent and unified approach to risk assessment for all endpoints. Invited participants from government, industry, and academia discussed focus questions in the areas of mode of action as the basis for harmonization, common levels of adverse effect across toxicities for use in dose-response assessments, and scaling and uncertainty factors. This report summarizes the results of those discussions. There was broad agreement, albeit not unanimous, that current science supports the development of a harmonized set of principles that guide risk assessments for all toxic endpoints. There was an acceptance among the participants that understanding the mode of action of a chemical is ultimately critical for nondefault risk assessments, that common modes of action for different toxicities can be defined, and that our approach to assessing toxicity should be biologically consistent.

Animals↗
PubMed2000

Evaluation of biologically based dose-response modeling for developmental toxicity: a workshop report.

Biologically based dose-response (BBDR) modeling represents a novel approach for quantitative assessment of health risk by incorporating pharmacokinetic and pharmacodynamic characteristics of a chemical and by relating the immediate cellular responses to a cascade of aberrant biological actions that leads to detectable adverse outcomes. The quantitative relationship of each of the intervening events can be described in mathematical forms that are amenable for adjustment and extrapolation over a range of doses and across species. A team of investigators at the Reproductive Toxicology Division of the U.S. Environmental Protection Agency has explored the feasibility of BBDR modeling by examining the developmental toxicity of a known teratogen, 5-fluorouracil. A panel of researchers from academic and industrial laboratories, biomathematical modelers, and risk assessment scientists was convened in a workshop to evaluate the approaches undertaken by the EPA team and to discuss the future prospects of BBDR modeling. This report summarizes the lessons learned from one approach to BBDR modeling and comments from the panelists: while it is possible to incorporate mechanistic information into quantitative dose-response models for the assessment of health risks, the process is enormously data-intensive and costly; in addition, the confidence of the model is directly proportional to our current understanding of basic biology and can be enhanced only through the ongoing novel discoveries. More importantly, the extent of "uncertainty" (inherent with the default assumptions associated with the NOAEL or benchmark approach) reducible by BBDR modeling requires further scrutiny and comparison.

Abnormalities, Drug-Induced↗
PubMed2000

Identifying critical windows of exposure for children's health.

Several authors have considered the importance of exposure timing and how this affects the outcomes observed, but no one has systematically compiled preconceptional, prenatal, and postnatal developmental exposures and subsequent outcomes. Efforts were undertaken to examine the information available and to evaluate implications for risk assessment for several areas: a) respiratory and immune systems, b) reproductive system, c) nervous system, d) cardiovascular system, endocrine system, and general growth, and e) cancer. Major conclusions from a workshop on "Critical Windows of Exposure for Children's Health" included a) broad windows of sensitivity can be identified for many systems but detailed information is limited; b) cross-species comparisons of dose to target tissue and better data on the exposure-dose-outcome continuum are needed; c) increased interaction among scientific disciplines can further understanding by using laboratory animal results in designing epidemiological studies and human data to suggest specific laboratory studies on mechanisms and agent-target interactions; and d) thus far, only limited attention has been given to peripubertal/adolescent exposures, adult consequences of developmental exposures, and genome-environment interactions. More specific information on developmental windows will improve risk assessment by identifying the most sensitive window(s) for evaluation of dose-response relationships and exposure, evaluation of biological plausibility of research findings in humans, and comparison of data across species. In public health and risk management, information on critical windows may help identify especially susceptible subgroups for specific interventions.

Adolescent↗
PubMed1998

Non-cancer risk assessment for nickel compounds: issues associated with dose-response modeling of inhalation and oral exposures.

This report presents the results of noncancer dose-response modeling for inhalation and oral exposures to nickel compounds using the NOAEL/LOAEL and benchmark dose (BMD) approaches. Several key issues associated with the implementation of the BMD approach were examined. Primary among them are difficulties associated with use of data for which the dose-response shape is poorly defined: nonuniqueness of maximum likelihood estimates and lower bounds equal to zero. In addition, several generalizable properties of the "hybrid approach" for modeling continuous endpoints were identified. A hybrid modeling approach allows one to consider "biological significance" on an individual (rather than group) basis; differences between individual- and group-based biological significance in the definition of benchmark response (BMR) levels are elucidated. In particular, it is shown that BMDs defined using group-based BMRs may be more like LOAELs than NOAELs. Application of cross-chemical and cross-endpoint comparisons suggest that, for chronic inhalation exposure, nickel sulfate appears to be as toxic or more toxic than nickel subsulfide and nickel oxide, although the high response rates for the latter two compounds at the lowest chronically administered concentration make such conclusions problematic. A nickel reference concentration could be derived based on the most sensitive benchmark concentration for chronic inhalation exposure to nickel sulfate, 1.7 x 10(-3) mg Ni/m3 for lung fibrosis in male rats. Analyses of oral studies of nickel sulfate and nickel chloride suggest that an appropriate basis for the nickel oral reference dose would be a BMD of 4-5 mg Ni/kg/day, based on increased prenatal mortality. (Uncertainty factors were not determined and neither an RfD nor an RfC was derived in this paper.) The BMD approach provides appropriate quantitative support for toxicological judgment; this paper addresses specific issues associated with the role of the BMD approach in noncancer risk assessment. Resolution of these and other issues may require the accumulation of a number of case studies such as the one presented here.

Administration, Oral↗
PubMed1997

Terminology of developmental abnormalities in common laboratory mammals (version 1).

This paper presents the first version of an internationally-developed glossary of terms for structural developmental abnormalities in common laboratory animals. The glossary is put forward by the International Federation of Teratology Societies (IFTS) Committee on International Harmonization of Nomenclature in Developmental Toxicology, and represents considerable progress toward harmonization of terminology in this area. The purpose of this effort is to provide a common vocabulary that will reduce confusion and ambiguity in the description of developmental effects, particularly in submissions to regulatory agencies worldwide. The glossary contains a primary term or phrase, a definition of the abnormality, and notes, where appropriate. Selected synonyms or related terms, which reflect a similar or closely related concept, are noted. Nonpreferred terms are indicated where their usage may be incorrect. Modifying terms used repeatedly in the glossary (e.g., absent, branched) are listed and defined separately, instead of repeating their definitions for each observation. Syndrome names are generally excluded from the glossary, but are listed separately in an appendix. The glossary is organized into broad sections for external, visceral, and skeletal observations, then subdivided into regions, structures, or organs in a general overall head to tail sequence. Numbering is sequential, and not in any regional or hierarchical order. Uses and misuses of the glossary are discussed. Comments, questions, suggestions, and additions from practitioners in the field of developmental toxicology are welcomed on the organization of the glossary as well as on the specific terms and definitions. Updates of the glossary are planned based on the comments received.

Animals↗
PubMed1995

The evaluation of the developmental toxicity of hydrochlorothiazide in mice and rats.

Timed-pregnant CD-1 outbred albino Swiss mice and CD Sprague-Dawley rats were administered hydrochlorothiazide (HCTZ, USP) in corn oil by gavage during major organogenesis, Gestational Days (GD) 6 through 15. The doses administered were 0, 300, 1000, or 3000 mg/kg/day for mice and 0, 100, 300, or 1,000 mg/kg/day for rats. Maternal clinical status was monitored daily during treatment. At termination (GD 17, mice; GD 20, rats), confirmed pregnant females (20-27 per group, mice; 36-39 per group, rats) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed. However, clinical signs including dehydration, piloerection, lethargy, and single-day weight loss appeared to be dose-related. HCTZ had no effect on maternal weight gain or water consumption, gravid uterine weight, relative maternal liver weight, or relative maternal kidney weight. There was no definitive evidence of embryotoxicity or fetal toxicity for mice on GD 17. Thus, the no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was 3000 mg/kg/day. In rats, HCTZ had no effect on maternal survival, clinical signs, or water consumption. Clinical signs were not dose-related. Maternal weight gain during treatment was depressed at 1000 mg/kg/day. Gravid uterine weight and relative maternal liver weight were unaffected. Relative maternal kidney weight was slightly (7-8%) increased at all dose levels, but there was no evidence of a dose response. Thus, the maternal NOAEL for rats was 300 mg/kg/day, based on decreased maternal weight gain during treatment at 1000 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Dose-response assessments for developmental toxicity. IV. Benchmark doses for fetal weight changes.

Recently, most attention on the application of benchmark dose (BMD) techniques to toxicology data has focused on quantal measures of response. Before the advantages of the BMD approach can be exploited in the risk assessment process, it is important that continuous measures of response also be modeled appropriately. In this study, we examined a variety of approaches to estimating BMDs for a change in fetal weight following chemical exposure from a total of 85 developmental toxicity experiments. We modeled the change in the mean fetal weight of a litter in response to treatment using a continuous power model, as well as reductions in the weight of individual fetuses within litters (defined as falling below a preset level) using a log-logistic model which incorporates litter size as a covariable and considers intralitter correlations. For the litter-based approach, several methods of defining a benchmark effect (BME) were considered, including a percentage change in mean litter weight, a change in mean litter weight relative to variability in the control group, and a reduction in the mean litter weight to some point on the control group distribution curve. For the fetus-based approach, we examined several BME options on the cumulative frequency distribution of the control fetuses for defining a low weight fetus and calculated several levels of additional risk. BMDs for four litter-based BMEs (a difference of 5% in mean fetal weight, a decrease to the 25th percentile mean weight of control litters, a decrease in the mean weight by 2 standard errors, and a decrease of 0.5 standard deviation units) and two fetus-based BMEs (a 5% added risk of weighing less than the 5th percentile of control weights and a 10% added risk of weighing less than the 10th percentile) showed strong similarities to each other and to statistically derived NOAELs. In addition to providing comparison with the NOAEL as a reference value, these analyses provided confirmation of the advantages of the BMD approach over the NOAEL in terms of the influence of dose spacing and dose selection. Combined with our previous analyses of quantal endpoints of fetal effects, this information provides a firm basis upon which to implement the benchmark dose concept in developmental toxicity risk assessments.

Animals↗
PubMed1995

Benchmark Dose Workshop: criteria for use of a benchmark dose to estimate a reference dose.

The purpose of the Benchmark Dose Workshop was to assess the feasibility and implications of replacing the no observed adverse effect level (NOAEL) with a benchmark dose (BMD) when deriving reference doses and concentrations (RfDs and RfCs). The workshop participants supported the use of the BMD method to remove many of the limitations inherent in using the NOAEL approach. Participants endorsed in general the use of a BMD for all quantal noncancer health effects and endorsed in particular the BMD for assessing developmental toxicity based on data presented at the workshop. The discussions of implementation recognized the need to demonstrate that changing from a NOAEL to a BMD gives the risk manager more certain information on which to base decisions. Most participants agreed that the current NOAEL-derived RfDs and RfCs are sufficiently protective and should only be changed as data become available for estimating a BMD. It was recognized that to achieve general acceptance of the BMD approach, it will have to be applied to a variety of endpoints.

Animals↗
PubMed1995

The application of benchmark dose methodology to data from prenatal developmental toxicity studies.

The benchmark dose (BMD) concept was applied to 246 prenatal-developmental toxicity (DT) datasets from government, industry and commercial laboratories. Five modeling approaches were used, 2 generic and 3 specific to DT models. BMDs for both quantal and continuous data were compared with statistically derived no observed adverse effect levels (NOAELs) to determine similarities. Quantal (Q) endpoints included litter responses (e.g., one or more dead or malformed implants), and QBMDs were calculated using a Q Weibull (QW) model. Two types of continuous (C) data were modeled, the proportion of implants affected per litter, and the change in fetal weight (both mean and distribution); continuous power (CP) and DT models were used to calculate CBMDs. QBMDs for a 5% change in response (QBMD05) were 6-fold lower, on average, than the corresponding NOAEL. CBMD05s on average were similar to the corresponding NOAELs, and CBMD05s from different models were similar to each other. Including litter size but not threshold improved the fit of the DT models. For fetal weight data, specific cutoff values were used to calculate BMDs that were similar on average to the corresponding NOAELs: (1) changes from the control mean (5% of the mean, 25th percentile of the control distribution, or a decrease of 0.5 standard deviation), and (2) a 5 or 10% decrease in the proportion of fetuses below the 5th or 10th percentile, respectively, of the control distribution. These results support the use of BMDs as providing a more consistent basis for risk assessment than do NOAELs.

Animals↗
PubMed1994

The outcome and techniques of primary and secondary tracheoesophageal puncture.

OBJECTIVES: To evaluate the outcome of primary vs secondary tracheoesophageal puncture (TEP), in particular the effects of preoperative and postoperative radiotherapy on success and complication rates in primary TEPs, and to highlight modified surgical and management techniques. DESIGN: Retrospective study of case series. SETTING: Chevalier Jackson-Norris Center-Department of Otorhinolaryngology and Bronchoesophagology at Temple University Health Sciences Center Hospital, Philadelphia, Pa. PATIENTS: One hundred six consecutive patients underwent primary TEPs and 30 underwent secondary TEPs for voice restoration after laryngectomy for cancer over a period of 8 years with follow-ups ranging from 6 months to 8.5 years. The group given primary TEP also includes 19 patients who received radiation for cure and salvage laryngectomy and 75 who received full-course postoperative radiotherapy. INTERVENTION: Tracheoesophageal puncture and Blom-Singer prosthesis. MAIN OUTCOME MEASURES: Speech measures including (1) voice intensity, (2) pitch of speech, (3) duration of sustained phonation, and (4) rate of speech. RESULTS: A success rate of 93% was achieved in the group of patients given primary TEP regardless of radiotherapy. An 83% success rate was achieved with patients given secondary TEP. There were no major complications related to TEPs. CONCLUSIONS: Primary TEP for patients requiring total laryngectomy is highly recommended since a second operative procedure can be avoided and speech obtained rapidly. Postoperative radiotherapy does not increase the complication rate from TEP.

Adult↗
PubMed1994

Dose-response assessment for developmental toxicity. I. Characterization of database and determination of no observed adverse effect levels.

Developmental toxicity risk assessment currently relies on the estimation of reference doses (RfDDTs) or reference concentrations (RfCDTS) based on the use of no observed adverse effect levels (NOAELs) and uncertainty factors. The benchmark dose (BMD) has been proposed as an alternative basis for reference value calculations. A large database of 246 developmental toxicity experiments (Segment II-type studies) representing 1825 data subsets for various endpoints was compiled for use in comparing NOAEL and BMD approaches to developmental toxicity risk assessment. This paper describes the characteristics of the database used and the estimation of NOAELs using several approaches. For each endpoint evaluated, two NOAELs were calculated using the NOSTASOT procedure (Tukey et al., 1985). The first NOAEL calculation, the QNOAEL, was based on a quantal response where a litter was defined as "affected" if one or more fetuses or implants in the litter had the endpoint of interest. The second NOAEL calculation, the CNOAEL, was based on the proportion of fetuses or implants affected within each litter and was treated as a continuous response variable. Fifty-seven percent of the 246 experiments had at least one endpoint that showed a significant trend with dose. A total of 386 data sets were significant with respect to both the quantal and continuous test of trend. An additional 44 data sets were identified with significant trend only by the quantal approach whereas 177 additional data sets were identified with significant trend tests only by the continuous approach. Thus, the continuous approach appeared to be more powerful in detecting dose-related toxicity, but the patterns detected by the two approaches differed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Dose-response assessment for developmental toxicity. II. Comparison of generic benchmark dose estimates with no observed adverse effect levels.

Developmental toxicity risk assessment currently relies on the estimation of reference doses (RfDDTS) of reference concentrations (RfCDTS) based on the use of no observed adverse effect levels (NOAELS) divided by uncertainty factors (UFs). The benchmark dose (BMD) has been proposed as an alternative basis for reference value calculations. A large database of 246 developmental toxicity experiments representing 1825 endpoints related to dead implants or malformed fetuses has been compiled for use in evaluating alternative approaches to developmental toxicity risk assessment. Using this database we have compared two approaches for BMD estimation with each other and with corresponding statistically derived NOAELS. Comparisons have been based on proportion of affected litters (litters with one or more affected offspring, a quantal response variable) and on the proportion of affected offspring within each litter (a continuous response variable). A quantal Weibull model was used to calculate generic BMDs for the quantal response variable (QBMDs) and a continuous power model was used to calculate generic BMDs for the continuous response variable (CBMDs) at three levels of additional risk (10, 5, and 1%). CBMD05s (continuous benchmark doses for 5% risk) and CNOAELs (statistically derived NOAELs based on the continuous response variable) were similar, with over 98% of the data subsets having CBMD05 and CNOAEL values that differed by less than an order of magnitude. In contrast, QNOAELs tended to be greater than corresponding QBMD10s. The observed conservatism of the QBMD values relative to the corresponding CBMD values was attributed to two factors, lower maximum likelihood estimates for the quantal model and wider confidence intervals around the maximum likelihood estimates, compared to the continuous model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗