Hershey Medical Center Technical Workshop Report: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings

Case Study Report: Business Case for Implementing Battery-Powered Tools for Direct-Bury Line Workers at an Electric Power Utility

Cutting cable and crimping compression connections are the two most commonly performed tasks by direct-bury line workers who repair and bury underground cable for electric power utilities. Battery-powered tools, rather than manual (Figure 1), do the demanding work of cutting cable and crimping connectors while the worker holds the tool in place. The focus of this study is whether the cost of battery-powered tools for direct-bury line workers can be justified on injury and illness data and other factors

Physiologically based pharmacokinetic modeling of arsenic in the mouse

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process. [Authors]]]> eng oai:serval.unil.ch:BIB_814 2022-02-19T02:25:05Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_814 Shenyang apprend à gérer ses pauvres. Kernen, A info:eu-repo/semantics/article article 1997 Perspectives Chinoises, vol. 40, pp. 17-21 fre oai:serval.unil.ch:BIB_8140284AD5C8 2022-02-19T02:25:05Z openaire documents urnserval <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_8140284AD5C8 Mitochondrial respiratory states and rate info:doi:10.26124/mitofit:190001.v2 info:eu-repo/semantics/altIdentifier/doi/10.26124/mitofit:190001.v2 Gnaiger, E. Aasander Frostner, E. Abdul Karim, N. Abumrad, NA. Acuna-Castroviejo, D. Adiele, RC. Ahn, B. Ali, SS. Alton, L. Alves, MG. Amati, F. Amoedo, ND. Andreadou, I. Arago, M. Aral, C. Arandarcikaite, O. Armand, AS. Arnould, T. Avram, VF. Bailey, DM. Bajpeyi, S. Bajzikova, M. Bakker, BM. Barlow, J. Bastos Sant'Anna Silva, AC. Batterson, P. Battino, M. Bazil, J. Beard, DA. Bednarczyk, P. Bello, F. Ben-Shachar, D. Bergdahl, A. Berge, RK. Bergmeister, L. Bernardi, P. Berridge, MV. Bettinazzi, S. Bishop, D. Blier, PU. Blindheim, DF. Boardman, NT. Boetker, HE. Borchard, S. Boros, M. Borsheim, E. Borutaite, V. Botella, J. Bouillaud, F. Bouitbir, J. Boushel, RC. Bovard, J. Breton, S. Brown, DA. Brown, GC. Brown, RA. Brozinick, JT. Buettner, GR. Burtscher, J. Calabria, E. Calbet, JA. Calzia, E. Cannon, DT. Cano Sanchez, M. Canto, AC. Cardoso, LHD. Carvalho, E. Casado Pinna, M. Cassar, S. Cassina, AM. Castelo, MP. Castro, L. Cavalcanti-de-Albuquerque, JP. Cervinkova, Z. Chabi, B. Chakrabarti, L. Chakrabarti, S. Chaurasia, B. Chen, Q. Chicco, AJ. Chinopoulos, C. Chowdhury, SK. Cizmarova, B. Clementi, E. Coen, PM. Cohen, BH. Coker, RH. Collin, A. Crisostomo, L. Dahdah, N. Dalgaard, LT. Dambrova, M. Danhelovska, T. Darveau, CA. Das, AM. Dash, RK. Davidova, E. Davis, MS. De Goede, P. De Palma, C. Dembinska-Kiec, A. Detraux, D. Devaux, Y. Di Marcello, M. Dias, TR. Distefano, G. Doermann, N. Doerrier, C. Dong, L. Donnelly, C. Drahota, Z. Duarte, FV. Dubouchaud, H. Duchen, MR. Dumas, JF. Durham, WJ. Dymkowska, D. Dyrstad, SE. Dyson, A. Dzialowski, EM. Eaton, S. Ehinger, J. Elmer, E. Endlicher, R. Engin, AB. Escames, G. Ezrova, Z. Falk, MJ. Fell, DA. Ferdinandy, P. Ferko, M. Ferreira, JCB. Ferreira, R. Ferri, A. Fessel, JP. Filipovska, A. Fisar, Z. Fischer, C. Fischer, M. Fisher, G. Fisher, JJ. Ford, E. Fornaro, M. Galina, A. Galkin, A. Gallee, L. Galli, GL. Gama Perez, P. Gan, Z. Ganetzky, R. Garcia-Rivas, G. Garcia-Roves, PM. Garcia-Souza, LF. Garipi, E. Garlid, KD. Garrabou, G. Garten, A. Gastaldelli, A. Gayen, J. Genders, AJ. Genova, ML. Giovarelli, M. Goncalo Teixeira da Silva, R. Goncalves, DF. Gonzalez-Armenta, JL. Gonzalez-Freire, M. Gonzalo, H. Goodpaster, BH. Gorr, TA. Gourlay, CW. Granata, C. Grefte, S. Guarch, ME. Gueguen, N. Gumeni, S. Haas, CB. Haavik, J. Haendeler, J. Haider, M. Hamann, A. Han, J. Han, WH. Hancock, CR. Hand, SC. Handl, J. Hargreaves, IP. Harper, ME. Harrison, DK. Hassan, H. Hausenloy, DJ. Heales, SJR. Heiestad, C. Hellgren, KT. Hepple, RT. Hernansanz-Agustin, P. Hewakapuge, S. Hickey, AJ. Ho, DH. Hoehn, KL. Hoel, F. Holland, OJ. Holloway, GP. Hoppel, CL. Hoppel, F. Houstek, J. Huete-Ortega, M. Hyrossova, P. Iglesias-Gonzalez, J. Irving, BA. Isola, R. Iyer, S. Jackson, CB. Jadiya, P. Jana, PF. Jang, DH. Jang, YC. Janowska, J. Jansen, K. Jansen-Duerr, P. Jansone, B. Jarmuszkiewicz, W. Jaskiewicz, A. Jedlicka, J. Jespersen, NR. Jha, RK. Jurczak, MJ. Jurk, D. Kaambre, T. Kaczor, JJ. Kainulainen, H. Kampa, RP. Kandel, SM. Kane, DA. Kapferer, W. Kappler, L. Karabatsiakis, A. Karavaeva, I. Karkucinska-Wieckowska, A. Kaur, S. Keijer, J. Keller, MA. Keppner, G. Khamoui, AV. Kidere, D. Kilbaugh, T. Kim, HK. Kim, JKS. Klepinin, A. Klepinina, L. Klingenspor, M. Klocker, H. Komlodi, T. Koopman, WJH. Kopitar-Jerala, N. Kowaltowski, AJ. Kozlov, AV. Krajcova, A. Krako Jakovljevic, N. Kristal, BS. Krycer, JR. Kuang, J. Kucera, O. Kuka, J. Kwak, HB. Kwast, K. Laasmaa, M. Labieniec-Watala, M. Lagarrigue, S. Lai, N. Land, JM. Lane, N. Laner, V. Lanza, IR. Laranjinha, J. Larsen, TS. Lavery, GG. Lazou, A. Lee, HK. Leeuwenburgh, C. Lehti, M. Lemieux, H. Lenaz, G. Lerfall, J. Li, PA. Li Puma, L. Liepins, E. Liu, J. Lopez, LC. Lucchinetti, E. Ma, T. Macedo, MP. Maciej, S. MacMillan-Crow, LA. Majtnerova, P. Makarova, E. Makrecka-Kuka, M. Malik, AN. Markova, M. Martin, DS. Martins, AD. Martins, JD. Maseko, TE. Maull, F. Mazat, JP. McKenna, HT. McKenzie, M. Menze, MA. Merz, T. Meszaros, AT. Methner, A. Michalak, S. Moellering, DR. Moisoi, N. Molina, AJA. Montaigne, D. Moore, AL. Moreau, K. Moreira, BP. Moreno-Sanchez, R. Mracek, T. Muccini, AM. Munro, D. Muntane, J. Muntean, DM. Murray, AJ. Musiol, E. Nabben, M. Nair, KS. Nehlin, JO. Nemec, M. Neufer, PD. Neuzil, J. Neviere, R. Newsom, SA. Nozickova, K. O'Brien, KA. O'Gorman, D. Olgar, Y. Oliveira, B. Oliveira, MF. Oliveira, MT. Oliveira, PF. Oliveira, PJ. Orynbayeva, Z. Osiewacz, HD. Pak, YK. Pallotta, ML. Palmeira, CM. Parajuli, N. Passos, JF. Passrugger, M. Patel, HH. Pavlova, N. Pecina, P. Pedersen, TM. Pereira da Silva Grilo da Silva, F. Pereira, SP. Perez Valencia, JA. Perks, KL. Pesta, D. Petit, PX. Pettersen, IKN. Pichaud, N. Pichler, I. Piel, S. Pietka, TA. Pino, MF. Pirkmajer, S. Plangger, M. Porter, C. Porter, RK. Procaccio, V. Prochownik, EV. Prola, A. Pulinilkunnil, T. Puskarich, MA. Puurand, M. Radenkovic, F. Ramzan, R. Rattan, SIS. Reboredo, P. Renner-Sattler, K. Rial, E. Robinson, MM. Roden, M. Rodriguez, E. Rodriguez-Enriquez, S. Roesland, GV. Rohlena, J. Rolo, AP. Ropelle, ER. Rossignol, R. Rossiter, HB. Rubelj, I. Rybacka-Mossakowska, J. Saada, A. Safaei, Z. Saharnaz, S. Salin, K. Salvadego, D. Sandi, C. Saner, N. Sanz, A. Sazanov, LA. Scatena, R. Schartner, M. Scheibye-Knudsen, M. Schilling, JM. Schlattner, U. Schoenfeld, P. Schots, PC. Schulz, R. Schwarzer, C. Scott, GR. Selman, C. Shabalina, IG. Sharma, P. Sharma, V. Shevchuk, I. Shirazi, R. Shiroma, JG. Siewiera, K. Silber, AM. Silva, AM. Sims, CA. Singer, D. Singh, BK. Skolik, R. Smenes, BT. Smit

Comparison of tissue dosimetry in the mouse following chronic exposure to arsenic compounds

Several chronic bioassays have been conducted in multiple strains of mice in which various concentrations of arsenate or arsenite were administered in the drinking water without a tumorigenic effect. However, one study (Ng et al., 1999) reported a significant increase in tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. A physiologically based pharmacokinetic model for arsenic in the mouse has previously been developed (Gentry et al., 2004) to investigate potential differences in tissue dosimetry of arsenic species across various strains of mice. Initial results indicated no significant differences in blood, liver, or urine dosimetry in B6C3F1 and C57Bl/6 mice for acute or subchronic exposure. The current work was conducted to compare model-predicted estimates of tissue dosimetry to additional kinetic information from the (C57Bl/6 x CBA)F1 and TgAc mouse. The results from the current modeling indicate that the pharmacokinetic parameters derived based on information in the B6C3F1 mouse adequately describe the measured concentrations in the blood/plasma, liver, and urine of both the (C57Bl/6 x CBA)F1 and TgAc mouse, providing further support that the differences in response observed in the chronic bioassays are not related to strain-specific differences in pharmacokinetics. One significant finding was that no increases in skin or lung concentrations of arsenic species in the (C57Bl/6 x CBA)F1 strain were observed following administration of low concentrations (0.2 or 2 mg/L) of arsenate in the drinking water, even though differences in response in the skin were reported. These data suggest that pharmacodynamic changes may be observed following exposure to arsenic compounds without an observable change in tissue dosimetry. These results provided further indirect support for the existence of inducible arsenic efflux in these tissues. <br /