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Review Articles

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    Phenylketonuria
    (2004-06-19) Matalon, Reuben; Michals-Matalon, Kimberlee; Surendran, Sankar; Tyring, Stephen K.
    Genome research is emerging as a new and important tool in biology used to obtain information on gene sequences, genomic interaction, and how genes work in concert to produce the final syndrome or phenotype. Defect in phenylalanine hydroxylase (PAH) gene result in Phenylketonuria (PKU). Molecular studies using the brain of the mouse model for PKU (PAHenu2) showed altered expression of several genes including upregulation of orexin A and a low activity of branched chain aminotransferase. These studies suggest that a single gene (PAH) defect is associated with altered expression, transcription and translation of other genes. It is the combination of the primary gene defect, the altered expression of other genes, and the new metabolic environment that is created, which lead to the phenotype.
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    A concept for maximum exposure levels in cars
    (2004-06-17) Hengstler, Jan G.; Schupp, Thomas
    Emission of volatile organic substances (VOC) from articles inside a car may lead to adverse health effects in exposed drivers. Presently, no general concept to derive maximum exposure levels inside cars has been published. Therefore, we recommend techniques for three types of maximum exposure levels inside cars, namely for (i) chronic exposure to non-genotoxic substances (ELIA, chronic), (ii) short term exposure inside automotive vehicles (STELIA) and (iii) genotoxic substances acting by threshold mechanisms (ELIA, cm). For derivation of the ELIA, chronic, we recommend to start with a Lowest Observed Adverse Effect Level (LOEL) or a Benchmark Dose 10 (BMD10) and use a procedure including four steps: a. estimation of the No Observed Effect Level (NOEL), b. extrapolation from laboratory animal to man, c. extrapolation to the general population due to interindividual differences and d. extrapolation to continuous exposure. To derive STELIAs a three-step-procedure is recommended, starting with a LOEL and a. estimating the NOEL, b. extrapolating from animal to man and c. extrapolating to the general population. Derivation of ELIA, cm, the maximum exposure level for carcinogens acting by a threshold mechanism, is certainly the most problematic procedure. We recommend to start with the lower 95% confidence limit for the most sensitive tumor type known in animals (BMD05) and a. extrapolate from animal to man and b. use a safety factor of 1/50 000 unless specific research succeeded in demonstrating specific levels of thresholds. It must be considered that a general concept for maximum exposure levels can not replace an intelligent toxicological approach considering the mechanism of action of individual substances. However, the strategy suggested here offers a practical technique for identification of individual problematic exposures that require an intensive toxicological evaluation.