The conundrum of unmeasured confounding: Comment on: “Can some of the detrimental neurodevelopmental effects attributed to lead be due to pesticides? by Brian Gulson”.
Lanphear BP, Hornung RW, Khoury J, Dietrich KN, Cory-Slechta DA, Canfield RL.
Cincinnati Children’s Environmental Health Center, Department of Pediatrics and of Environmental Health, Cincinnati Children’s Hospital Medical Center, The University of Cincinnati, Cincinnati, Ohio, USA. bruce.lanphear@cchmc.org Sci Total Environ. 2008 Jun 25;396(2-3):196-200. Epub 2008 Mar 7. Comment on: Sci Total Environ. 2008 Jun 25;396(2-3):193-5.
The problem described by Dr. Brian Gulson – confounding by unmeasured exposures to pesticides – is only the most recent in a series of potential confounders cited to explain the observed effect of lead on children’s intellectual abilities or behavioral problems. Despite the persistent problem of unmeasured confounders, there are several lines of evidence implicating lead as a toxicant at blood lead levels <10 microg/dL. First, in striking contrast with pesticides, there is considerable evidence from numerous studies linking low-level lead exposure with cognitive deficits and behavioral problems, even after controlling for a variety of potential confounders. Second, the consistency of evidence from diverse cohorts and distinct, if not always directly measured potential confounders – enhances our confidence that the lead effect observed at blood lead levels <10 microg/dL is not attributable to unmeasured confounders. Third, in our reanalysis of the Rochester Lead Study, the inclusion of parent-reported mouthing behaviors and breastfeeding status did not attenuate the effect of lead exposure on children’s intellectual function. Finally, although we can never entirely dismiss unmeasured confounding in observational studies, we can rely on experimental studies of lead-exposed animals to confirm that lead is a toxicant. Thus, while we must remain vigilant for unmeasured or poorly measured confounders, it is crucial to balance the endless search for confounders with the evidence of toxicity and the need to take action to protect public health. The alternative, to perpetually permit children to be exposed to lead and other emerging toxicants, is both absurd and unacceptable.
Guidelines for developmental neurotoxicity and their impact on organophosphate pesticides: a personal view from an academic perspective.
Slotkin TA. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu Neurotoxicology. 2004 June:25(4):631-40.
The appropriate regulation of drugs, chemicals and environmental contaminants requires the establishment of clear and accepted guidelines for developmental neurotoxicity. Ideally, these guidelines should encompass the ability to assess widely disparate classes of compounds through routine tests, with high throughput and low cost. Increasingly, however, the progress in primary research from academic laboratories deviates from this goal, focusing instead on categorizing novel effects of toxicants, development of new testing paradigms, and extension of techniques into molecular biology. The differing objectives of academic science as opposed to those of regulatory agencies or industry, are driven in part, by the priorities of the agencies that fund primary research. Recent work on organophosphate pesticides (OPs) such as chlorpyrifos (CPF) illustrate this dichotomy. Originally, OPs were thought to affect brain development through their ability to elicit cholinesterase inhibition and consequent cholinergic hyperstimulation. This common mechanism allowed for parallels to be drawn between standard measures of systemic toxicity, gross morphological examinations, and exposure testing utilizing an easily-assessed surrogate endpoint, plasma cholinesterase activity. In the past decade, however, it has become increasingly evident that CPF, and probably other OPs, have direct effects on cellular processes that are unique to brain development, and that these effects are mechanistically unrelated to inhibition of cholinesterase. The identification and pursuit of these mechanisms and their consequences for brain development represent new and exciting scientific findings, while at the same obscuring the ability to sustain a uniform approach to neurotoxicity guidelines or biomarkers of exposure. In the future, a new set of test paradigms, relying on primary work in cell culture, invertebrates, or non-mammalian models, followed by more targeted examinations of specific processes in mammalian models, may unite cutting-edge academic research with the need for establishing flexible guidelines for developmental neurotoxicity.
In utero exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) and neurodevelopment among young Mexican American children.
Eskenazi B, Marks AR, Bradman A, Fenster L, Johnson C, Barr DB, Jewell NP.
Center for Children’s Environmental Health Research, School of Public Health, University of California, Berkeley, 2150 Shattuck Ave, Suite 600, Berkeley, California 94720-7380, USA. eskenazi@berkeley.edu Pediatrics. 2006 Jul;118(1):233-41.
OBJECTIVE: We investigated the relationship between prenatal exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) and neurodevelopment of Mexican farm-workers’ children in California.
METHODS: Participants from the Center for the Health Assessment of Mothers and Children of Salinas study, a birth cohort study, included 360 singletons with maternal serum measures of p,p’-DDT, o,p’-DDT, and p,p’-DDE. Psychomotor development and mental development were assessed with the Bayley Scales of Infant Development at 6, 12, and 24 months.
RESULTS: We found a approximately 2-point decrease in Psychomotor Developmental Index scores with each 10-fold increase in p,p’-DDT levels at 6 and 12 months (but not 24 months) and p,p’-DDE levels at 6 months only. We found no association with mental development at 6 months but a 2- to 3-point decrease in Mental Developmental Index scores for p,p’-DDT and o,p’-DDT at 12 and 24 months, corresponding to 7- to 10-point decreases across the exposure range. Even when mothers had substantial exposure, breastfeeding was usually associated positively with Bayley scale scores. CONCLUSIONS: Prenatal exposure to DDT, and to a lesser extent DDE, was associated with neurodevelopmental delays during early childhood, although breastfeeding was found to be beneficial even among women with high levels of exposure. Countries considering the use of DDT should weigh its benefit in eradicating malaria against the negative associations found in this first report on DDT and human neurodevelopment.
In utero exposure to DDT and performance on the Brazelton neonatal behavioral assessment scale.
Fenster L, Eskenazi B, Anderson M, Bradman A, Hubbard A, Barr DB.
California Department of Health Services, Division of Environmental and Occupational Disease Control, 850 Marina Bay Parkway, Richmond, CA 94804-6403, USA. lfenster@dhs.ca.gov Neurotoxicology. 2007 May;28(3):471-7. Epub 2007 Jan 10.
We investigated whether decrements in neonatal neurodevelopment, as determined by the Brazelton neonatal behavioral assessment scale (BNBAS), were associated with in utero exposure to dichlorodiphenyltrichloroethane (DDT): p,p’-dichlorodiphenyl trichloroethane (p,p’-DDT), o,p’-dichlorodiphenyl trichloroethane (o,p’-DDT) and p,p’-DDT’s primary breakdown product p,p’-dichlorodiphenyl dichloroethylene (p,p’-DDE) (heretofore collectively referred to as DDT/DDE). Our subjects were a birth cohort of 303 infants whose mothers were low-income Latinas living in the Salinas Valley, an agricultural community in California. We assessed neonates < or =2 months old using the seven BNBAS clusters (habituation, orientation, motor performance, range of state, regulation of state, autonomic stability, and reflex) and examined performance in relationship to DDT/DDE measures in maternal serum samples collected during pregnancy. We did not find any detrimental associations between in utero DDT/DDE levels and neonatal performance on the BNBAS. In this same cohort, we previously demonstrated that exposures to DDT/DDE were related to decrements in neurodevelopment at 6-24 months of age. The failure to observe effects on the BNBAS in these same children may be due to limited sensitivity of a single BNBAS assessment or a delay in the manifestations of neurodevelopmental effects of DDT/DDE until after the neonatal period.
Pesticide toxicity and the developing brain.
Eskenazi B, Rosas LG, Marks AR, Bradman A, Harley K, Holland N, Johnson C, Fenster L, Barr DB. Center for Children’s Environmental Health Research, School of Public Health, University of California, Berkeley, CA 94704, USA. eskenazi@berkeley.edu Basic Clin Pharmacol Toxicol. 2008 Feb;102(2):228-36.
Organochlorine pesticides are used in some countries for malaria control and organophosphate pesticides are widely used in agriculture and in homes. Previous literature documents children’s exposure to these chemicals both in utero and during development. Animal studies suggest that many of these chemicals are neurodevelopmental toxicants even in moderate doses, but there are few studies in human beings. Associations of children’s pesticide exposure with neurodevelopment from studies being conducted worldwide are summarized. In addition, we present the work of the CHAMACOS study, a longitudinal birth cohort study of Mexican-American children living in the Salinas Valley of California. In this study, we investigated the relationship of children’s neurodevelopment with maternal dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene serum levels, as well as prenatal and child organophosphate urinary metabolite levels. We have examined the association with children’s performance on the Brazelton Neonatal Assessment Scales and at 6, 12 and 24 months on the Bayley Scales of Infant Development (mental development and psychomotor development) and mothers report on the Child Behaviour Checklist. We observed a negative association of prenatal dichlorodiphenyltrichloroethane exposure and child mental development. We also observed adverse associations of prenatal but not postnatal organophosphate pesticide exposure with mental development and pervasive developmental disorder at 24 months.
Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk?
Cory-Slechta DA. Environmental and Occupational Health Sciences Institute, A joint Institute of Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA. dcs@eohsi.rtugers.edu Neurotoxicology. 2005 Aug;26(4):491-510
Despite the fact that virtually all chemicals exposure of humans are to mixtures, and that these mixed exposures occur in the context of numerous other risk modifiers, our current understanding of human health risks is based almost entirely on the evaluation of chemicals studied in isolation. This paper describes findings from our collaborative studies that prompt questions about these approaches in the context of neurotoxicology. The first section describes studies investigating the interactions of maternal Pb exposure with maternal stress. Examined across a range of outcome measures, it shows that maternal Pb can modulate the effects of maternal stress, and, conversely, stress modifies the effects of Pb. Further, effects of Pb+stress could be detected in the absence of an effect of either risk factor alone, and, moreover, the profile of effects of Pb alone differs notably from that of Pb+stress. Collectively, interactions were not systematic, but differed by brain region, gender and outcome measure. A second section describes outcomes of studies examining combined exposures to the pesticides paraquat (PQ) and maneb (MB) during development which likewise reveal potentiated effects of combined exposures. They also demonstrate examples of both progressive and cumulative neurotoxicity, including a marked vulnerability following gestational exposure to MB, to the effects of PQ, a pesticide with no structural relationship to MB. The ability of current hazard identification and risk assessment approaches to adequately identify and encompass such effects remains an important unanswered question. One consideration proposed for further evaluating potential interactions that may be of significance for the nervous system is based on a multi-hit hypothesis. It hypothesizes that the brain may readily compensate for the effects of an individual chemical itself acting on a particular target system, but when multiple target or functional sites within that one system are attacked by different mechanisms (i.e., multiple chemical exposures or chemical exposures combined with other risk factors), homeostatic capabilities may be restricted, thereby leading to sustained or cumulative damage.