Use of physiologically based pharmacokinetic modeling to investigate individual versus population risk.

Because of the heterogeneity of the human population, it is generally expected that there will be a broad range of observed susceptibilities to the biological effects of exposure to chemicals or drugs. Often it is possible to distinguish specific classes of individuals, such as infants or the elderly, who appear to be more susceptible to a specific effect. Non-cancer risk assessment often address this variability by dividing the experimentally determined acceptable exposure level by an uncertainty factor of 10 to protect sensitive individuals; cancer risk assessments typically do not address this issue in any quantitative fashion. Physiologically based pharmacokinetic (PBPK) modeling provides the capability to quantitatively describe the potential impact of pharmacokinetic factors on the variability of individual risk. In particular, PBPK models can be used to determine the impact of differences in key metabolism enzymes, whether due to multiple genotypic expression, such as cytochrome P450 polymorphisms, or just due to normal variation in enzyme activities within the general population. Other potential modulators of sensitivity which can be addressed quantitatively with a PBPK model include physical condition, level of activity, disease states, age, hormonal status, and interactions with other chemicals and drugs. In each case, the PBPK model provides a quantitative structure for determining the effect of these various factors on the relationship between the external (environmental) exposure and the internal (biologically effective) target tissue exposure. When coupled with Monte Carlo analysis, the PBPK model provides a method to assess the quantitative impact of these sources of variability on individual risk (as opposed to average population risk) by comparing model-predicted risks over the distribution of individual parameter values.

Genotypic toxicity: implications for individuals and populations.

The goals of genetic ecotoxicology are discussed and redefined. New directions in which genotoxicity "effect" studies might be pursued are outlined. Recognition of the genotoxic disease syndrome in lower animals suggests that more attention should be given to exploring the relationships between DNA damage (adduct formation, gene mutations, etc.) and its manifestation at the level of individuals. Within a given population, not all individuals are equally susceptible to pollutant toxicity (including genotoxicity). It is proposed therefore, that more attention be paid to identifying the factors underlying interindividual variability in susceptibility. Examples are provided of specific cases in which differences in susceptibility to pollutants have been directly related to genotypic predisposition. This approach is also advocated for investigating the individual and population level consequences of genotoxic damage. The possibility of using phenotypic traits to recognise subsets of individuals within populations possessing similar genotypes is discussed.

Population genetic structure and ecotoxicology.

Electrophoretic analyses of population genetic structure, both in the laboratory and in the field, have documented significant shifts in allozyme genotype frequencies in a variety of aquatic taxa as a result of environmental impacts. Studies are documented which indicate that contaminants may select for individuals with tolerant allozyme genotypes, causing the potential loss of individuals with sensitive genotypes. This may diminish the genetic variability and fitness of affected populations and make them more susceptible to extinction following a subsequent stress. Future research involving population genetic structure and ecotoxicology should focus on determining the mechanism of sensitivity, documenting multigenerational effects of chronic laboratory exposure on population genetic composition, investigating whether previously stressed and genetically impacted populations are more susceptible to further natural and/or anthropogenic stressors, and establishing the utility of population genetic structure as a sensitive monitor of impacts in aquatic systems and their subsequent remediation.

[The detection of mutations arising in human populations]. / Obnaruzhenie mutatsii, voznikaiushchikh v populiatsiiakh cheloveka.

The problem on screening of de novo mutations, arising in populations, by the method of search for rare protein variants has been critically discussed. The data on monomorphic loci and rare variants of human blood proteins, and platelet monoamine oxidase previously not studied in terms of populations are presented. A method is suggested to screen mutations, using restriction analysis of mitochondrial DNA in mouse populations.

[Dynamics of the genetic structure in experimental Drosophila populations for the Adh locus as affected by ethanol]. / Dinamika geneticheskoi struktury éksperimental'nykh populiatsii drozofily po lokusu Adh pod vliianiem étanola.

Electrophoresis method was used to analyze the genetic structure of four experimental Drosophila populations (the control one and those with 5, 10 and 15% of ethanol in the nutrient medium) with initial frequency of AdhF = 0.5 for 50 monitoring generations. It was established that F and S alleles had different selective values. Natural selection favoured the F-allele. Addition of ethanol to the nutrient medium increased the selection intensity in the first 15 generations but did not change the relative adaptability of three genotypes. This caused a similarity of genetic structure in experimental populations during 50 generations.

[Population genetics analysis of the association of sensitivity to phenylthiocarbamide and nervous system strength]. / Populiatsionno-geneticheskii analiz assotsiatsii chuvstvitel'nosti k feniltiokarbamidu i sily nervnoi sistemy.

The results of gene pool analysis of three Daghestan isolates for mendelian markers and multifactorial characters are presented. The neurodynamic status of persons with tt and T-phenotypes for sensitivity to phenylthiocarbamide is characterized.

[Taste sensitivity for phenylthiocarbamide among the population of western Kazakhstan]. / Vkusovaia chuvstvitel'nost' k feniltiokarbamidu sredi naseleniia Zapadnogo Kazakhstana.

The sensitivity to phenyl thiocarbamide was studied in 405 people of Kazakh nationality and in 161 people of Russian nationality (males and females), the students of the Institute. 23.9% of the former proved non-sensitive, the gene frequency "t" being 0.490. Among the latter these values were 28.6% and 0.535, respectively.

[Population biology aspects of arthropod control]. / Populationsbiologische Aspekte der Arthropodenbekämpfung.

The present problems of the still predominating chemical control of pests (resistance, side effects) cannot only be compensated by improved active ingredients, formulations, or modes of application. New concepts are of increasing importance. Recent advancements in the field of ecology and genetics of populations are very useful in this respect. Especially the laws of dynamics in abundance and dispersion are of fundamental importance for a selective and effective control. Experiences in population genetics enable us to have a more comprehensive idea of the origin of qualitative alterations in populations, e.g. of resistance. This provides possibilities of derive resistance-preventing measures and test them in the field. To secure a sufficient decrease in abundance without exerting too high a selection pressure in a single direction a scheduled change or a combination of different means of control is desirable, characteristics of the "Integrated Control" or of the "Pest Management".

[Effectiveness of selection for thorax length in model Drosophila populations in chemical mutagen exposure]. / Effektivnost' otbora po dline grudi v model'nykh populiatsiiakh drozofily pri vozdeistvii khimicheskim mutagenom.

Artificial selection for increasing and decreasing Drosophila thorax length was carried out over 20 generations. Chemical mutagen, dimethylsulfate (DMS) was regularly applied to enhance genetic variation in selected lines. It was determined that under the influence of mutagen the efficiency of selection for decreasing thorax length was much higher, while selection course for increasing thorax length was not affected significantly. Regression coefficient of responses to selection, general for males and females, was equal to b = -0.035 +/- 0.004 for lines of negative direction of selection when the mutagen was applied and -b = -0.023 +/- 0.004 without mutagenesis; for lines of positive direction b = 0.026 +/- 0.005 and b = 0.024 +/- 0.005. Fitness component variation by artificial selection was studied. A complex correlation was detected between direction of selection, the shift value of model quantitative character and fitness component variation by selection. The main factor stimulating a sharp drop of average fitness of lines appeared to be the influence of directional artificial selection. The regular treatment by a moderate dose of the mutagen did not affect markedly the average fitness variation of selected lines.

[Sulfalene pharmacogenetics. II. The population genetic aspect]. / Farmakogenetika sul'falena. Soobshchenie II. Populiatsionno--geneticheskii aspekt.

Half-life of sulfalen, a new antibacterial drug, with the biotransformation, performed by means of microsomal acetyltransferase, has been studied in 53 individuals of Moscow Russian population. The absence of sex dimorphism for the trait studied is demonstrated. Distribution of individuals according to values of the pharmacokinetic parameter mentioned within the population is bimodal with the correlation of phenotypic frequencies of "rapid" and "slow" inactivators--72 and 28%. Possible causes of discrepancies between the observed sulfalen inactivator frequencies and similar data on isoniazid are discussed.

[Results of a cytogenetic examination of population groups with intensive and limited use of pesticides]. / Rezul'taty tsitogeneticheskogo obsledovaniia grupp naseleniia pri intensivnom i ogranichennom ispol'zovanii pestitsidov.

Cytogenetic examination was carried out in two representative groups of teenagers living in zones with intense and limited use of pesticides. The average frequency of chromosome aberrations in the experimental zone was 1.35%, which exceeded significantly that in the control group. The found cytogenetic effect shows a potential genetic hazard of intense use of pesticides for the population.

[Mechanism of the heterogeneity of a staphylococcal population with respect to methicillin resistance]. / K mekhanizmu geterogennosti stafilokokkovoi populiatsii poustoichivosti k metitsillinu

The study of the staphylococcal population heterogeneity with respect to methicillin resistance by 2 methods revealed different numbers of the resistant cells in the population. Thus, when the microbial suspension was plated on an agarized medium with methicillin (50 gamma/ml), only 0.0007--0.0005 per cent of the resistant cells were found. When the colonies were replicated from a medium without methicillin to a medium containing methicillin (50 gamma/ml), 84.3--97.3 per cent of the resistant microbial cells were found in the population of the same strains. The main mechanism in the heterogeneity of the staphylococcal population with respect to methicillin resistance was impairement of the phenotype manifestation of the antibiotic resistance under definite conditions.

[Transduction transmission of the extrachromosomal markers of antibiotic resistance in staphylococcal populations]. / Transduktsionnaia peredacha vnekhromosomnykh markerov ustoichivosti k antibiotikam v stafilokokkovykh populiatsiiakh

Transduction of extrachromosomal markers of resistance to penicillin and erythromycin in staphylococcal strains isolated from patients was studied. Two transduction methods were compared, i. e. transduction with a phage filtrate of the donor culture resistant to erythromycin and transduction on mixed cultivation of the donor and recipient. A higher transduction rate was observed with the latter method. Mixed cultivation of the donor cultures resistant to penicillin or erythromycin and the recipient strains of the wild type sensitive to these antibiotic resulted in transduction of the respective markers. Transductants which acquired prophage 6 simultaneously with marker Egg became donors of erythromycin resistance.