Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals (2017) / Chapter Skim
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4 Effect of Polybrominated Diphenyl Ethers on Neurodevelopment
4 Effect of Polybrominated Diphenyl Ethers on Neurodevelopment
Pages 115-152
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From page 115... ...
. The cla is compris of 209 con ass sed ngeners that s share a bromi inated diphenyl ether molecu with up to 10 bromine atoms attach (see Figu 4-1)
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The committee judged that a systematic review of animal studies on PBDE exposure and neurodevelopmental outcomes would be an appropriate complement to that review of the human literature. Because the committee's goal was to identify end points that could be considered relevant for human intelligence and ADHD and other attentionrelated behavioral conditions, the committee's systematic review of the animal data focused on PBDE studies that measured learning, memory, attention, and response inhibition.
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Examples of tests include Morris water maze, radial arm maze, and operant tests of cognition. BOX 4-2 PECO Statement for the PBDE (Human)
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. Animal Evidence For the independent systematic review of the animal evidence, scientific literature databases were searched for relevant studies on the effects of developmental exposure to PBDEs on measures of learning, memory, attention, or response inhibition in nonhuman mammals.
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. FIGURE 4-2 Steps in the Navigation Guide protocol.
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that might affect the magnitude and even the direction of the apparent effect. Internal validity or risk of bias was assessed for individual animal studies using the OHAT method that outlines an approach to evaluating risk of bias for experimental animal studies (NTP 2015)
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The basis for determining the ratings is similar in the two methods and involves a similar process of giving an initial rating to the evidence and then considering factors that could upgrade or downgrade the rating. All human observational studies start out with an initial moderate rating in the Navigation Guide method, and the initial confidence rating assigned to studies in the OHAT method depends on aspects of study design (see Figure 4-3)
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. Low Level of Evidence There is low confidence in the body of evidence for an association bet e f n tween exposure to the subst tance and the heealth outcome(s)
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. RESULTS R Lite erature Searc and Scree ch ening Results s Animal Studies S A seearch for recen published systematic reviews on de ntly evelopmental exposure to PBDEs and a l alterations in le earning, memmory, attention or response inhibition in nonhuman m n, e n mammals fou no releva re und ant views.
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; study did not report experimental PBDE exposure (n = 1) ; study did not include developmental exposure (n = 1)
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; study did not quantify developmental exposure to PBDE as concentration measured in human biological samples (n = 1) ; study did not report quantitative measure of intelligence, ADHD, or attention-related behavioral problems (n = 4)
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. Two studies in rats found several indications of decreased learning in the Morris water maze (e.g., prolonged latency to find 126
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2008 BDE-99 Mouse (NMRI) PND 10 4 and 6 months Morris water maze; radial arm maze 0, 0.8 Llansola et al.
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2013 BDE-209 Mouse (Swiss albino) PND 3-10 PND 60-66 Morris water maze; radial arm maze 0, 20 Verma et al.
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Nevertheless, a meta-analysis (presented later in this chapter) of rodent studies on several BDEs, including BDE-47, and latency in the last learning trial of the Morris water maze showed consistent evidence of an association between developmental exposure to PBDEs and decrements in this one measure.
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Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE 4-8 Risk of bi heatmap of studies of BD ias f DE-47 and lear rning in roden In HAWC: https://hawcp nts. project.
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2001 NMRI mice PND 10 5 months Morris water maze 10.5 None He et al. 2009 Sprague- Dawley rats PND 10 2 months Morris water maze None 1 Eriksson et al.
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. The results of the three studies on learning were inconsistent and used different tests (Morris water maze, radial maze, and visual discrimination)
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The two studies of DE-71 effects on memory had inconsistent results and were evaluated in rats of different ages and with different tests (Morris water maze and radial maze)
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NOTE: Studies were available on six BDE congeners and one technical grade mixture. All the BDEs had studies of learning, six had studies of memory, and only the mixture had studies of attention; no studies of response inhibition were found for any of the congeners.
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Overall, there is consistent evidence of an increase in latency in the last trial of the Morris water maze that is robust to multiple sensitivity analyses. Nevertheless, the evidence of a dose-response gradient across all PBDE congeners is tempered by the fact that there is no statistically significant trend in log10(dose)
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. T section d lth ves This describes the c committee's eevaluations in the sequence they occurred and includ a descripti of the dra systematic review by L t d, des ion aft c Lam et al., the co ommittee's ev valuation of it, the committtee's update, and a discu , ussion of the u updated Lam et al.
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After screen e . ning the resul 12 studies met the incl lts, s lusion criteria of the PECO statement; nin studies measured IQ an seven stud evaluated ADHD and/ at f s ne nd dies d /or tention-reelated behavio condition (see Appe oral ns endix F, Secti F-4)
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Under the Navigation Guide, the confidence (or "quality") of the body of evidence was rated as moderate and the strength of evidence was considered sufficient1 by the authors and was translated by the committee to a "moderate" level of evidence to support an inverse association between PBDEs and IQ following the OHAT method.
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MECHANISTIC EVIDENCE The mechanisms of action through which developmental exposure to PBDEs alters neurobehavioral outcomes, such as IQ or attention in children or learning and memory in rodents, are not well understood. Nevertheless, data from mechanistic studies conducted in vitro or in animal models can help establish the biological plausibility of the associations that have been observed between PBDE exposure during the perinatal period and later behavioral outcomes.
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A meta-analysis of learning data found consistent evidence of an effect, measured as latency in the last trial of the Morris water maze. Thus, the moderate confidence rating translates to a moderate level of evidence that developmental exposure to these congeners is associated with decrements in learning in rodents.
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; BDNF, brain-derived neurotrophic factor; CAMKII, calmodulin-dependent kinase II; DA, dopamine; GABA, gamma-aminobutyric acid; GAP-43, growth-associated protein; IP3, 1,4,5-triphosphate; LTP, long-term potentiation; nACh-R, nicotine acetylcholine; NMDAR, glutamate receptor; RyR, ryanodine receptor; T4, thyroxine; TH, thyroid hormone; TR, thyroid hormone receptor. a Ibhazehiebo et al.
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Very low confidence ratings were given to BDE-203 and -206 and to DE-71, which means there is an inadequate level of evidence to assess whether exposure to these congeners or to the technical mixture is associated with decrements in learning in rodents. Memory There is low confidence in the body of evidence on developmental exposure to PBDEs and effects on memory in rodents on the basis of evidence on BDE-47, -153, and -209.
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In general, measurement of IQ in children relies on welldescribed test methods that have been validated for broad use in biomedical research. The committee's evaluation of the animal data found that, unlike the case of IQ testing in people, standardized test batteries, animal models, and exposure regimens were not used in the animal studies.
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Meta-analysis: The committee found that the meta-analyses were valuable in summarizing data from the systematic reviews and in comparing the animal and human evidence in a robust and consistent manner. The meta-analysis of a subset of animal studies that tested learning in ro dents exposed to various BDEs provided evidence of a possible relationship between PBDEs and decrements in learning that was not evident when the data sets on the individual BDEs were evaluated qualitatively.
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Using an Existing Systematic Review: The committee critically evaluated a recent systematic review of epidemiologic studies on the effect of developmental exposure to PBDEs on IQ and ADHD and judged it to be adequate for use in the context of the review question. This evalua tion allowed the committee to focus its efforts on updating the literature search of the recent re view.
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Hazard Identification The committee concluded that developmental exposure to PBDEs is presumed to pose a hazard to intelligence in humans and that it was not possible to draw a hazard conclusion about effects on attention-related behavioral conditions in humans. Low-Dose Effects The committee concluded that the human studies provide a moderate level of evidence that PBDEs are associated with decrements in IQ in humans.
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2014. Developmental exposure to the polybrominated diphenyl ether PBDE 209: Neurobehavioural and neuroprotein analysis in adult male and female mice.
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direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous sys tem.
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2011. Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced purkinje cell dendrite arboriza tion by polybrominated diphenyl ethers.
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2007. Measurement of polybrominated diphenyl ethers and metabolites in mouse plasma after exposure to a commercial pentabromodiphenyl ether mixture.
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2009. Metabolism of polybrominated diphenyl ethers (PBDEs)
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2015. The developmental neu rotoxicity of polybrominated diphenyl ethers: Effect of DE-71 on dopamine in zebrafish larvae.
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