4. In a cross-sectional study of PFOA and kidney function (as measured by the gl

Question

4. In a cross-sectional study of PFOA and kidney function (as measured by the glomerular filtration rate, or GFR), the data suggest that serum PFOA is higher when the GFR is lower, suggesting that PFOA may decrease kidney function. Can you think of an alternative association? Consider that PFOA is excreted primarily via the kidneys 5. You conduct a case-control study of breast cancer, and you find that higher SES is a risk factor for breast cancer. It is known that having any children is associated with lower breast cancer risk, and that having more children is associated with lower risk than having fewer children. Do you think that the finding of more risk in women of higher SES might be due to confounding? How would you address this question in your analysis?

Explanation / Answer

4. Perfluoroalkyl acids (PFOA) are synthetic compounds widely used in industrial and commercial applications. Laboratory studies suggest that these persistent and bioaccumulative chemicals produce oxidant stress and damage glomerular endothelial cells, raising concern regarding the impact of these compounds on renal function.

Perfluoroalkyl acids (PFAAs) are synthetic organic compounds with a totally fluorinated carbon chain of varying length and a negatively charged functional group, such as carboxylic or sulfonic acid. This imparts high stability and thermal resistance to these compounds. PFAAs have found wide utility when polymerized in stain-resistant sprays for carpets and upholstery, fire-retarding foams, and nonstick cooking surfaces and food packagings, such as microwave popcorn bags and pizza packaging. National biomonitoring surveys reveal that >98 % of the US population have detectable levels of PFAAs in the blood including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS) and perfluorononanoic acid (PFNA).

In cell culture studies, exposure of microvascular endothelial cells to PFOS induces endothelial permeability through increased production of reactive oxidative species at concentrations relevant to human exposures. This is important given that endothelial cells are vital to structure and function of the glomeruli in the kidney. Furthermore, endothelial permeability plays a critical role in the ischemic renal injury. The effect of PFOA, PFOS, PFNA and PFHxS on the kidneys is further magnified by the fact that these compounds are well absorbed orally but have poor renal elimination rates and half-lives in humans of 2.3-8.5 years. Children and adolescents are uniquely vulnerable to PFOA and PFOS as they have greater food consumption per pound body weight. PFAAs are present in human breast milk, and serum levels in children are generally higher than in adults. Childhood exposure may present the additional risk of disrupting cardiovascular and renal physiologic functions, and so vulnerability may be greater than in adults.

Cross-sectional studies have associated PFOA biomarkers with reduced renal function. In one recent large, community-based study of residents living near a fluoropolymer production facility which resulted in contamination of their drinking water with elevated PFOA, serum PFOA, PFOS, PFNA and PFHxS concentrations were inversely correlated with estimated glomerular filtration rate (eGFR) in otherwise healthy children and adolescents. A study by Shankar et al revealed similar findings in adults. The study also found that PFOA and PFOS were associated with increased odds of chronic kidney disease (CKD), defined as eGFR <60 ml/min/1.73 m2.

Several cross-sectional epidemiological studies in adults and children have also shown a positive association between PFOA and uric acid (UA), though one failed to detect such an association. This is relevant since hyperuricemia has long been thought to be an important marker of renal disease. Moreover, growing evidence suggests that hyperuricemia may be part of the causal pathway in the development of hypertension. Numerous clinical studies have shown that elevated UA levels are associated with increased risk of hypertension, independent of other risk factors. UA levels >5.5 mg/dL were observed in 90 % of adolescents with essential hypertension, whereas UA levels were significantly lower in controls and teens with either white-coat or secondary hypertension. Finally, hyperuricemia is an independent risk factor for disease progression in pediatric patients with CKD.

However, studies to date have not explored the association between low-grade exposure to perfluoroalkyl chemicals in the range commonly experienced by children/adolescents and kidney function. Therefore, we examined the association of PFOAs with kidney function i.e., eGFR and uric acid in a nationally representative sample of US adolescents. We sought to test the hypothesis that higher levels of exposure to PFOAs would be associated with a decrement in kidney function and an increment in serum uric acid concentration.

In this cross-sectional study of healthy adolescents, it has been found that the levels of PFOA and PFOS to be significantly associated with decreased kidney function within the normal range and increased serum UA levels. Prospective studies are needed to confirm the association and understand biological mechanisms underlying this relationship.

5. Breast cancer incidence rates have been shown to be higher in areas of high socioeconomic status (SES) than in more disadvantaged areas. A number of observational studies have also found breast cancer incidence to be greater among women with higher individual-level SES, and this relation appears to be due in part to the distribution of predisposing factors such as late age at first birth, low parity, and menopausal female hormone use. It is unclear whether the increased incidence of breast cancer in higher SES neighborhoods is due to characteristics of the neighborhoods themselves or to the fact that greater proportions of women in those areas have high personal-level SES.

Only 2 studies, both white women, have considered individual-level and neighbourhood-level SES simultaneously. In a Wisconsin case-control study of 7,179 cases of breast cancer and 7,488 controls, the odds of having breast cancer were 20% greater in the highest quintile of neighbourhood SES relative to the lowest after control for individual-level SES and breast cancer risk factors. In a Massachusetts case-control study of 548 cases and 490 controls, the odds of breast cancer were 30% greater for those living in the wealthiest areas relative to the poorest areas and about 20% greater for those with the highest level of education relative to those with the lowest.

At the same levels of education and income, African-American women are more likely than their white counterparts to live in neighbourhoods of low SES. Thus, it may be more feasible to disentangle the individual effects of personal and neighbourhood-level SES on breast cancer incidence by studying African-American women. We have done so based on data from the Black Women's Health Study, a follow-up study of women from across the United States. In addition to assessing overall breast cancer incidence, we assessed estrogen receptor-positive (ER+) and estrogen receptor-negative (ER) breast cancer separately, because their associations with breast cancer risk factors may differ.

Not breastfeeding or weaning prematurely is associated with health risks for mothers as well as for infants. Epidemiologic data suggest that women who do not breastfeed face higher risk of breast cancer and ovarian cancer, as well as obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease. As in the pediatric literature, most evidence arises from observational studies, which are subject to confounding by other health behaviors. For maternal health outcomes, associations are generally reported according to lifetime duration across all pregnancies, rather than duration of feeding for each pregnancy.

Some studies have suggested that breastfeeding reduces breast cancer risk, but evidence has been mixed. Observational studies relating lactation and breast cancer among postmenopausal women have largely failed to identify an association. Reports from case-control studies suggest a modest inverse association between breastfeeding and premenopausal breast cancer risk, but findings have been inconsistent and limited by potential recall bias. Longitudinal studies have similarly produced conflicting results. A meta-analysis of 47 studies found that each year of breastfeeding was associated with a 4.3% (95% CI, 2.9–5.8) reduction in risk of invasive breast cancer. In the Nurses’ Health Study II, the association was stronger among women with a first-degree relative with breast cancer. In this group, never breastfeeding was associated with a 2.4-fold increase (95% CI, 1.3–4.5) in the incidence of premenopausal breast cancer, compared with ever having breastfed.

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