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C A Kimmel

Publications and source records attributed to C A Kimmel.

At least 19 recordsLinked to original sources
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↗
PubMed1994

Dose-response assessment for developmental toxicity. III. Statistical models.

Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for determining reference doses and reference concentrations. Statistical models appropriate for representing the unique features of developmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, M. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. Howe, J. Chen, and D. Gaylor, 1991, Risk Anal. 11, 583-590). Generalizations of those models (designated the RVR, LOG, and NCTR models, respectively) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome; and the possibility of a threshold dose below which background response rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. Litter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a beta-binomial distribution for the observations among individual fetuses. In contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse effect levels determined by statistical tests of trend. Greater emphasis on and further examination of dose-response modeling for developmental toxicity testing are needed; biologically based approaches that consider the continuum of developmental effects induced in such tests should be encouraged.

Animals↗
PubMed1993

Skeletal development following heat exposure in the rat.

The effects of gestation day (GD) 10 heat exposure in the rat were studied to determine the temperature-response relationship for the induction of skeletal and other defects. Conscious pregnant rats (Experiment 1) were exposed to various temperatures in a warm air chamber. Body temperature was measured using a rectal probe, and these measurements were confirmed as representing core body temperature in separate animals using telemetric procedures. Those animals whose core body temperature was raised to 41-41.9 degrees C had over 90% malformed pups (examined at postnatal day (PND) 3), and a 25% reduction in the percent of live pups per litter. Animals whose temperature was raised to 39.2-40.9 degrees C had a low incidence of pups with similar types of malformations. The primary types of malformations were of the axial skeleton, consisting of fusions and other abnormalities of the ribs and vertebral elements, and a decrease in the total number of ribs and centra. The acute maternal effects of these temperature increases were signs of heat exhaustion during and 1-2 hr after exposure, but there were no permanent changes in weight gain or other signs. When temperatures were raised to > or = 42 degrees C, all maternal animals died. In a second study (Experiment 2), pregnant rats (from a different supplier) were anesthetized to determine the effect of reducing maternal stress and were exposed to heat as in Experiment 1. Those animals whose core body temperature was raised to 42-42.5 degrees C for 5 min had pups with similar responses to those in Experiment 1 at 41-41.9 degrees C, although the reduction in litter size was not as great. Animals whose temperature was raised to 41 degrees C had a much lower incidence of pups with similar defects, and animals whose temperature was raised to 43 degrees C did not survive. A more detailed analysis of the skeletal defects in Experiment 2 showed rib and vertebral malformations that appear to be related to the stage of somite development at the time of exposure.

Animals↗
PubMed1993

Embryonic development in vitro following short-duration exposure to heat.

Gestation day (GD) 10 rat embryos (10-12 somites) were exposed in vitro for 10 to 25 minutes at 42 or 43 degrees C and evaluated 24 hrs later for alterations in growth and specific morphological parameters, using a modified Brown-Fabro (Brown and Fabro: Teratology, 24:65-78, '81) scoring system that allowed evaluation of development relative to gestational age. At 42 degrees C, crown-rump length appeared to be particularly sensitive, responding to only 10 mins exposure. A 15-min exposure resulted in decreased total protein, somite number and morphological score. No system was uniquely sensitive, since all parameters demonstrated some degree of response. Rather, systems affected were those that would be developing most rapidly at this time in gestation. At 43 degrees C, all of the parameters measured were affected by a 10-min exposure. These results demonstrate alterations in vitro after much shorter exposure periods than previously reported on GD10, which may be due, in part, to the use of a modified scoring system that permitted the evaluation of graded individual end point changes relative to gestational age. The response patterns demonstrated a clear temperature- and exposure duration-dependency, with a shift from a more shallow duration-response curve to a more dramatic inhibition of development as temperature increased from 42 degrees C to 43 degrees C.

Animals↗
PubMed1993

Statistical model for fetal death, fetal weight, and malformation in developmental toxicity studies.

The purpose of this paper is to present a statistical model for analyzing the joint effects of exposure on fetal death, fetal weight, and malformation in a developmental toxicity study. In addition to allowing for the usual litter effect, the model allows for correlations between different outcomes measured on the same fetus. Fitting the model requires first focusing on non-live outcomes by modeling the probability of fetal death or resorption as a function of dose. Then outcomes among live fetuses are modeled using a two-stage regression approach. The first stage models fetal weight as a function of dose and the second stage models fetal malformation as a function of dose, as well as residuals from the weight model. The regression coefficients from the malformation model have intuitive interpretations in terms of correlations between littermates and between different outcomes measured within the same fetus. Not only does the approach provide a useful way to investigate the relationship between adverse fetal outcomes, it also yields a natural framework for conducting quantitative risk assessment. A procedure is proposed for quantifying overall risk by incorporating the three outcomes in order to estimate safe dose levels and corresponding lower confidence limits. The method is illustrated using data from an experiment in mice conducted through the National Toxicology Program.

Abnormalities, Drug-Induced↗
PubMed1993

Relationship between abnormal somite development and axial skeletal defects in rats following heat exposure.

The effects of in vivo heat exposure on gestation day (GD) 10 rat embryos were evaluated on GD 11 to determine the relationships between morphological sequelae following in vivo and in vitro exposures and between effects detected on GD 11 and those observed in postnatal day (PND) 3 pups. Anesthetized rats were exposed to 42 degrees C in a warm air incubator until their rectal temperatures reached 41 degrees C or until a rectal temperature of 42-42.5 degrees C had been maintained for 5 minutes. Heat-exposed embryos exhibited a significant decrease in growth parameters including head length, somite number, and protein content/embryo versus controls. These changes correlated well with in vitro effects from an earlier study (G.L. Kimmel et al., '93). Among the morphological endpoints which were slightly delayed in development were the caudal neural tube, branchial bars, forelimb and hindlimb. The only effect on the embryos that could not be explained as a transient delay in development induced by heat was the induction of unsegmented somites. Additional embryos were exposed to 42 degrees C for 15-20 min in vitro and examined specifically for unsegmented somites, which were observed in 47% of embryos exposed to 42 degrees C in vivo or in vitro. This phenomenon was observed in somites 9-20, i.e., those that give rise to cervical and thoracic vertebrae and ribs. These results correlated well with the axial skeletal malformations observed in PND 3 pups exposed to the same heat treatment (C.A. Kimmel et al., '93).

Animals↗