CANADA: Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort

There are more than 7 million PFAS and over 21 million fluorinated compounds listed in PubChem (2023).
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CANADA: Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort

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Goodman CV, Till C, Green R, El-Sabbagh J, Arbuckle TE, Hornung R, Lanphear B, Seguin JR, Booij L, Fisher M, Muckle G, Bouchard MF, Ashley-Martin J - "Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort" Neurotoxicol Teratol 98:107181 (2023) doi: 10.1016/j.ntt.2023.107181
https://www.sciencedirect.com/science/a ... 6223000314

Abstract

Background: Exposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce.

Objective: To quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex.

Methods: We measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics.

Results: Geometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10-2.50), 4.97 (3.20-6.20) and 1.09 (0.67-1.60) μg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p < .01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = -2.80, 95% CI: -4.92, -0.68; PFOS: B = -2.64, 95% CI: -4.77, -0.52; PFHxS: B = -2.92, 95% CI: -4.72, -1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = -3.16, 95% CI: -4.90, -1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: -0.99, 2.26). No significant associations were found for EF in either males or females.

Conclusions: Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific.
Last edited by pfpcnews on Sun Jun 04, 2023 8:21 am, edited 1 time in total.
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Re: CANADA: Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort

Post by pfpcnews »

I don't usually comment on news items, but some things came to mind, reading this new study from the York researchers, and now being a bit familiar with the MIREC data.

Re: GFR (glomerular filtration rate) - never examined in fluoride studies (See: PFPC Member post #5105 - viewtopic.php?f=30&t=4334&p=5105)

Goodman et al.:"Some studies measured PFAS in samples collected later in pregnancy (Goudarzi et al., 2017; Oh et al., 2021; Spratlen et al., 2020; Wang et al., 2015) when physiological changes occur such as plasma volume expansion or changes in glomerular filtration rate which can result in exposure misclassification (Aguree and Gernand, 2019; Faupel-Badger et al., 2007; Savitz and Wellenius, 2018; Verner et al., 2015)."

"Furthermore, we were unable to control for parental IQ or pregnancy physiology such as glomerular filtration rate or plasma volume expansion which can impact prenatal PFAS concentrations (Sagiv et al., 2015). However, given that our measures of PFAS were from trimester one of pregnancy, these physiological changes of pregnancy are less likely to be major confounders (Aguree and Gernand, 2019)."

Why was GFR never considered in the fluoride/creatinine studies?

Why was fluoride not considered a covariate?

Iodine intake? TPOAb?

Were those with thyroid dysfunction excluded? If not, why not? All this data is available.

Co-author Lanphear had previously reported that adults with high TPOAb (a marker of autoimmune hypothyroidism, commonly seen in situations of high iodine intake) may represent a vulnerable subgroup in regard to PFAS's adverse effects on thyroid hormone (Webster et al., 2016).

Many MIREC women (16%) have elevated TPOAb (too-high iodine consumption, see Hall et al., 2023) - why wasn't that considered? [It should be noted that Webster et al. ignorantly only considered iodine deficiency, not excessive iodine intake (also omitted by York authors in their previous work.)]

Once again, the choice of confounders is remarkable, observing what was NOT included...

Regarding the question of GFR being "less likely" to be of concern in the first trimester - MIREC women were tested at 11.6 weeks gestation (range: 2–14).

Studies have shown that GFR can increase by approximately 40-50% above non-pregnant values during the first trimester (Lopes van Balen et al., 2019).

Sagiv et al. (2017, used as a reference by Goodman et al.), wrote, in fact:
"For markers of pregnancy hemodynamics, all PFAS concentrations were higher for women with blood drawn earlier in pregnancy, lower prenatal GFR and higher prenatal plasma albumin levels...In addition, overall PFAS concentrations declined over the enrollment period, and were lower for participants with no history of smoking, higher GFR and lower plasma albumin levels...we observed lower PFAS concentrations with higher GFR (estimated using creatinine) and lower albumin. This is the first epidemiologic study to show associations of PFASs with GFR in pregnant women, and we hypothesize that these associations may be due to higher flow rate of filtered fluid through the kidney...It may also be appropriate to adjust for albumin, as well as GFR, in multivariable models when estimating associations for PFASs with health outcomes, depending on the relationship between these physiologic markers and the outcome. For example, a recent study that used a pharmacokinetic model to examine the impact of GFR on PFAS-birth weight associations reported results for simulations that suggested that associations were substantially attenuated due to confounding by GFR."
It's hard to take any of the York work seriously anymore.

RJ, co-admin

Lopes van Balen VA, van Gansewinkel TAG, de Haas S, Spaan JJ, Ghossein-Doha C, van Kuijk SMJ, van Drongelen J, Cornelis T, Spaanderman MEA - "Maternal kidney function during pregnancy: systematic review and meta-analysis" Ultrasound Obstet Gynecol 54(3):297-307 (2019) doi: 10.1002/uog.20137
https://obgyn.onlinelibrary.wiley.com/d ... /uog.20137

Sagiv SK, Rifas-Shiman SL, Webster TF, Mora AM, Harris MH, Calafat AM, Ye X, Gillman MW, Oken E - "Sociodemographic and Perinatal Predictors of Early Pregnancy Per- and Polyfluoroalkyl Substance (PFAS) Concentrations" Environ Sci Technol 49(19):11849-58 (2017) doi: 10.1021/acs.est.5b02489
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638415/

Of interest:

Verner MA, Loccisano AE, Morken NH, Yoon M, Wu H, McDougall R, Maisonet M, Marcus M, Kishi R, Miyashita C, Chen MH, Hsieh WS, Andersen ME, Clewell HJ 3rd, Longnecker MP - "Associations of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK)" Environ Health Perspect 123(12):1317-24 (2015) doi: 10.1289/ehp.1408837
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671243/

Webster GM, Rauch SA, Marie NS, Mattman A, Lanphear BP, Venners SA - "Cross-Sectional Associations of Serum Perfluoroalkyl Acids and Thyroid Hormones in U.S. Adults: Variation According to TPOAb and Iodine Status (NHANES 2007-2008)" Environ Health Perspect 124(7):935-42 (2016) doi: 10.1289/ehp.1409589
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937851/

Liu R, Liu H, Ni S, Wei J, Chen Y, Men K, Zhang J, Liu L, Yang Z, Tang N - "Associations between exposure to perfluoroalkyl substances and estimated glomerular filtration rate in population without kidney disease" Journal of Environmental and Occupational Medicine 40(4): 448-455 (2023) doi: 10.11836/JEOM22403
"Serum PFHxS exposure was negatively correlated with eGFR in non-renal disease populations, and this negative association was more pronounced in women."

Bonefeld-Jørgensen EC, Boesen SAH, Wielsøe M, Henriksen TB, Bech BH, Halldórsson ÞI, Long M - "Exposure to persistent organic pollutants in Danish pregnant women: Hormone levels and fetal growth indices" Environ Toxicol Pharmacol 99:104108 (2023). doi: 10.1016/j.etap.2023.104108
"Higher level of PFAA was associated with higher thyroid and androgen levels. The PFAA did not associate with estrogens. Higher thyroid-peroxidase-antibody (TPO-Ab) and estradiol level associated with higher birth weight and length in sons. For daughters, the TPO-Ab associations were the opposite being inversely associated with birth weight and length, and higher TPO-Ab and estradiol associated with lower gestational age. Mediation analyses suggested that TPO-Ab mediates the association of PFAA with FGI."
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