Kannan Krishnan

Guidelines for the communication of Biomonitoring Equivalents: Report from the Biomonitoring Equivalents Expert Workshop

Biomonitoring Equivalents (BEs) are screening tools for interpreting biomonitoring data. However, the development of BEs brings to the public a relatively novel concept in the field of health risk assessment and presents new challenges for environmental risk communication. This paper provides guidance on methods for conveying information to the general public, the health care community, regulators and other interested parties regarding how chemical-specific BEs are derived, what they mean in terms of health, and the challenges and questions related to interpretation and communication of biomonitoring data. Key communication issues include: (i) developing a definition of the BE that accurately captures the BE concept in lay terms, (ii) how to compare population biomonitoring data to BEs, (iii) interpreting biomonitoring data that exceed BEs for a specific chemical, (iv) how to best describe the confidence in chemical-specific BEs, and (v) key requirements for effective communication with health care professionals. While the risk communication literature specific to biomonitoring is sparse, many of the concepts developed for traditional risk assessments apply, including transparency and discussions of confidence and uncertainty. Communication of BEs will require outreach, education, and development of communication materials specific to several audiences including the lay public and health care providers.

An algorithm for predicting tissue : Blood partition coefficients of organic chemicals from n‐octanol: Water partition coefficient data

The objectives of the present study were (1) to develop an algorithm to predict tissue:blood partition coefficients (PCs) of organic chemicals from n-octanol: water (Ko/w) PC data, and (2) to apply this algorithm to predict the rat tissue:blood PCs of some relatively hydrophilic organics, particularly ketones, alcohols, and acetate esters. The algorithm, developed by modifying a previously published one, involved predicting tissue:blood PCs of chemicals by dividing their partitioning into tissues by the sum of their partitioning into erythrocytes and plasma. The partitioning of a chemical into tissues, erythrocytes, and plasma was expressed as an additive function of its partitioning into neutral lipids, phospholipids, and water contained in them. The muscle, liver, and adipose tissue:blood PCs predicted with the present method were compared with the experimental values obtained from the literature for five ketones, eight alcohols, and eight acetate esters. The predicted muscle:blood and liver:blood PCs for the set of 21 hydrophilic organics were within a factor of 1.01 and 0.99 (on an average), respectively, of the experimental values. However, the predicted adipose tissue:blood PCs of the hydrophilic organics were greater than the experimental values by a factor of 4.13, which improved when vegetable oil:saline (Ko/s) PCs were used instead of Ko/w PCs (factor of 1.51). Overall, the use of the present algorithm should enable the prediction of tissue:blood PCs for organic chemicals for which Ko/w or Ko/s data are available.

A biologically-based algorithm for predicting human tissue: blood partition coefficients of organic chemicals

A biologically-based algorithm for predicting the tissue: blood partition coefficients (PCs) of organic chemicals has been developed. The approach consisted of (i) describing tissues and blood in terms of their neutral lipid, phospho lipid, and water contents, (ii) obtaining data on the solu bility of chemicals in n-octanol and water, and (iii) calcu lating the tissue: blood PCs by assuming that the solubility of a chemical in n-octanol corresponds to its solubility in neutral lipids, the solubility in water corresponds to the solubility in tissue/blood water fraction, and the solubility in phospholipids is a function of solubility in water and n- octanol. The adequacy of this approach was verified by compar ing the predicted values with previously published experi mental data on human tissue (liver, lung, muscle, kidney, brain, adipose tissue): blood PCs for 23 organic chemicals. In the case of liver, lung, and muscle, the predicted PC val ues were in close agreement with the higher-end of the range of experimental PC values found in the literature. The predicted brain: and kidney: blood PCs were greater than the experimental PCs in most cases by approximately a factor of two. Whereas the adipose tissue: blood PCs of relatively less hydrophilic chemicals were adequately pre dicted, the predicted PCs for relatively more hydrophilic chemicals were much greater than the experimentally- determined values. There was a good agreement between the predicted and experimentally-determined blood solubility of the 23 chemicals chosen for this study, indicating that the over- estimation of tissue:blood PCs by the present method is not due to under-estimation of blood solubility of chemicals. Rather, it might be due to the lower tissue solubility of chemicals observed experimentally due to the complexity of the tissue matrices. This novel approach of describing tissues in terms of the type of lipid and water content should enable the predic tion of the tissue:blood PCs of organic chemicals with information on their solubility in water and n-octanol, for developing physiologically-based toxicokinetic models.

Physiological Modeling of Age-Specific Changes in the Pharmacokinetics of Organic Chemicals in Children

Age-specific changes in the pharmacokinetics of chemicals are primarily due to differences in physiological and biochemical factors. For integrating the available information on the age-dependent changes in the physiological and biochemical factors, and for evaluating their combined influence on the pharmacokinetics of chemicals, physiologically based pharmacokinetic (PBPK) models are potentially useful. The objectives of this study were, therefore, (1) to assemble information on age-specific differences in physiological parameters such as alveolar ventilation rate, cardiac output, tissue volumes, tissue blood flow rates, and tissue composition for children of various age groups, and (2) to incorporate these data within a PBPK model for simulating the inhalation pharmacokinetics of a highly metabolized, volatile organic chemical (furan) in children of specific age groups (6, 10, and 14 yr old). The age-specific data on various physiological parameters were assembled following a review of the relevant literature and the hepatic metabolism rate of furan was set equal to the liver blood flow rate in adults and children. The blood:air and tissue:blood partition coefficients were calculated using molecular structure information along with the data on the blood and tissue composition (lipid and water contents) in children and adults. The PBPK model was used to simulate the pharmacokinetics of furan in adults and children (6, 10, and 14 yr old) exposed continuously for 30 h to 1 w g/L of this chemical in inhaled air. The model simulations suggest that, for the same exposure conditions, the blood concentration of furan is likely to be greater in children by a factor of 1.5 (at steady state) than in adults, and the maximal factor of adult-children differences in liver concentration of furan metabolite is about 1.25. The PBPK model framework developed in this study should be useful for predicting the adult-children differences in internal dose of chemicals for risk assessment applications.

Relative lipid content as the sole mechanistic determinant of the adipose tissue:blood partition coefficients of highly lipophilic organic chemicals

The adipose tissue:blood partition coefficient (PCat:b) refers to the ratio of chemical concentration or solubility in adipose tissue and blood. The solubility of a chemical in adipose tissue or whole blood is equal to the sum total of its solubility in lipid and water fractions of these matrices. For highly lipophilic organic chemicals (HLOCs, i.e., chemicals with log n-octanol:water partition coefficients (PCo:w) greater than four), their solubility in the water fractions of both tissue and blood is negligible, and therefore their solubility in lipid fractions of tissue and blood alone determines PCat:b. Since the numerical value representing chemical solubility in lipids is likely to be the same for both blood lipids and adipose tissue lipids, the PCat:b values should be hypothetically, equal to the ratio of lipid content of adipose tissue and blood. The objective of the present study was therefore to verify whether the PCat:bs of HLOCs (volatile organics, dioxins, PCBs, PBBs, DDT) are equal to the ratio of adipose tissue and blood lipid levels. The data on lipid content of rat and human blood and adipose tissues were obtained from the literature. The calculated tissue:blood lipid ratios were comparable to the human and rat PCat:b of volatile organic chemicals, dioxins, PCBs, PBBs and/or DDT obtained from the literature. These results then suggest that, regardless of the identity and PCo:w of HLOCs, their PCat:b is equal to the ratio of lipid in adipose tissues and blood.

CHARACTERIZATION OF AGE-RELATED CHANGES IN BODY WEIGHT AND ORGAN WEIGHTS FROM BIRTH TO ADOLESCENCE IN HUMANS

The pharmacokinetics and tissue dose of chemicals may differ among individuals of a population, particularly between adults and children. The adult-children differences in pharmacokinetics arise from age-related changes in the physiological, biochemical, and physicochemical determinants of uptake and disposition of chemicals. The objectives of this study were to review the published literature to assemble data on the human body weight and organ weights as a function of age (specifically between birth and 18 yr old) and to analyze these data, in order to develop regression equations for calculating body weight and organ weights of children using age as the dependent function. The specific organs/tissues for which the data on age-related weight were obtained and analyzed include blood, adipose tissues, liver, lungs, brains, heart, kidneys, spleen, the reproductive organs (male: prostate gland, seminal vesicle, testes, and epididymis; female: ovaries, uterus, and uterine tubes), glands (adrenal, pituitary, thymus, pancreas, and thyroid), bone marrow (total and red), intestinal tract, stomach, muscle, skin (epidermis and dermis), and skeleton. In both male and female children, the sum of these organs is systematically lower than the body weight, and this discrepancy may be resolved with the additional availability and consideration of data on hypodermis weight. The equations and data on body weight and organ weights presented in this article should be useful for constructing age-specific, physiologically based pharmacokinetic models for children.

A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals

The algorithms in the literature focusing to predict tissue:blood PC (P(tb)) for environmental chemicals and tissue:plasma PC based on total (K(p)) or unbound concentration (K(pu)) for drugs differ in their consideration of binding to hemoglobin, plasma proteins and charged phospholipids. The objective of the present study was to develop a unified algorithm such that P(tb), K(p) and K(pu) for both drugs and environmental chemicals could be predicted. The development of the unified algorithm was accomplished by integrating all mechanistic algorithms previously published to compute the PCs. Furthermore, the algorithm was structured in such a way as to facilitate predictions of the distribution of organic compounds at the macro (i.e. whole tissue) and micro (i.e. cells and fluids) levels. The resulting unified algorithm was applied to compute the rat P(tb), K(p) or K(pu) of muscle (n=174), liver (n=139) and adipose tissue (n=141) for acidic, neutral, zwitterionic and basic drugs as well as ketones, acetate esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons and ethers. The unified algorithm reproduced adequately the values predicted previously by the published algorithms for a total of 142 drugs and chemicals. The sensitivity analysis demonstrated the relative importance of the various compound properties reflective of specific mechanistic determinants relevant to prediction of PC values of drugs and environmental chemicals. Overall, the present unified algorithm uniquely facilitates the computation of macro and micro level PCs for developing organ and cellular-level PBPK models for both chemicals and drugs.

Molecular Structure-Based Prediction of the Partition Coefficients of Organic Chemicals for Physiological Pharmacokinetic Models

The objectives of the present study were (1) to develop and validate a methodology for predicting tissue:air (pt:a) and blood:air (Pb:a) partition coefficients (PCs) of organic chemicals from molecular structure information, and (2) to incorporate this methodology within physiologically based pharmacokinetic (PBPK) models to enable automated calculation of PCs from molecular structure information provided as input to the model. The proposed methodology involves (1) estimating n-octanol:water or oil:water (Po:w) PCs and water:air (Pw:a) PCs at 25°C of chemicals from their molecular structure information using previously validated fragment constant methods, (2) correcting for the temperature dependence of vapor pressures using the Clausius-Clapeyron equation to extrapolate the Pw:a to 37°C, and (3) incorporating these data along with data on volumes of neutral lipids, phospholipids, and water in tissues and blood in an algorithm to predict Pt:a and Pb:a. The predictions of rat and human Pt:a (liver, muscle,...

Database for Physiologically Based Pharmacokinetic (PBPK) Modeling: Physiological Data for Healthy and Health-Impaired Elderly

Physiologically based pharmacokinetic (PBPK) models have increasingly been employed in chemical health risk assessments. By incorporating individual variability conferred by genetic polymorphisms, health conditions, and physiological changes during development and aging, PBPK models are ideal for predicting chemical disposition in various subpopulations of interest. In order to improve the parameterization of PBPK models for healthy and health-impaired elderly (herein defined as those aged 65 yr and older), physiological parameter values were obtained from the peer-reviewed literature, evaluated, and entered into a Microsoft ACCESS database. Database records include values for key age-specific model inputs such as ventilation rates, organ volumes and blood flows, glomerular filtration rates, and other clearance-related processes. In total, 528 publications were screened for relevant data, resulting in the inclusion of 155 publications comprising 1051 data records for healthy elderly adults and 115 data records for elderly with conditions such as diabetes, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and renal disease. There are no consistent trends across parameters or their associated variance with age; the gross variance in body weight decreased with advancing age, whereas there was no change in variance for brain weight. The database contains some information to inform ethnic and gender differences in parameters; however, the majority of the published data pertain to Asian (mostly Japanese) and Caucasian males. As expected, the number of records tends to decrease with advancing age. In addition to a general lack of data for parameters in the elderly with various health conditions, there is also a dearth of information on blood and tissue composition in all elderly groups. Importantly, there are relatively few records for alveolar ventilation rate; therefore, the relationship between this parameter and cardiac output (usually assumed to be 1:1) in the elderly is not well informed by the database. Despite these limitations, the database represents a potentially useful resource for parameterizing PBPK models for the elderly to facilitate the prediction of dose metrics in older populations for application in risk assessment.

Approaches for Applications of Physiologically Based Pharmacokinetic Models in Risk Assessment

Physiologically based pharmacokinetic (PBPK) models are particularly useful for simulating exposures to environmental toxicants for which, unlike pharmaceuticals, there is often little or no human data available to estimate the internal dose of a putative toxic moiety in a target tissue or an appropriate surrogate. This article reviews the current state of knowledge and approaches for application of PBPK models in the process of deriving reference dose, reference concentration, and cancer risk estimates. Examples drawn from previous U.S. Environmental Protection Agency (EPA) risk assessments and human health risk assessments in peer-reviewed literature illustrate the ways and means of using PBPK models to quantify the pharmacokinetic component of the interspecies and intraspecies uncertainty factors as well as to conduct route to route, high dose to low dose and duration extrapolations. The choice of the appropriate dose metric is key to the use of the PBPK models for the various applications in risk assessment. Issues related to whether uncertainty factors are most appropriately applied before or after derivation of human equivalent dose (or concentration) continue to be explored. Scientific progress in the understanding of life stage and genetic differences in dosimetry and their impacts on variability in susceptibility, as well as ongoing development of analytical methods to characterize uncertainty in PBPK models, will make their use in risk assessment increasingly likely. As such, it is anticipated that when PBPK models are used to express adverse tissue responses in terms of the internal target tissue dose of the toxic moiety rather than the external concentration, the scientific basis of, and confidence in, risk assessments will be enhanced.