I. Bisphenol A
1.Pollution source
Bisphenol A is a synthetic chemical that connects 2 phenolic rings by joining 2 methyl groups to form a methyl bridge.
2.BPA
BPA is a synthetic estrogen, but is now widely used in the production of polycarbonate plastics and epoxy resins using its cross-linking properties, and is also present in intravenous catheters (including dialysis circulation lines). incomplete polymerization reactions and polymer degradation of BPA lead to its leaching into food and beer bottles and dental sealants.
Exposure to nanoconcentrations of BPA is nearly ubiquitous in a variety of daily life situations, including eating, breathing, and absorption through the skin, and is ultimately detected in the urine of 93% of adults. serum BPA levels are higher in male smokers and are negatively associated with their socioeconomic status.
A study that included 22 pre-dialysis patients with chronic kidney disease (CKD) found that serum BPA levels were negatively associated with kidney function. Dialysis patients had increased BPA exposure due to the almost daily use of dialysis catheters. BPA levels in hemodialysis and peritoneal dialysis patients were 5.3 ± 0.3 ng/ml and 3.8 ± 0.2 ng/ml, respectively, both higher than 2.6 ± 0.1 ng/ml in healthy controls. polysulfone membranes and polyester polymer alloy hollow fibers may increase BPA clearance.
3. Metabolism
Animal studies have shown that BPA can be rapidly and efficiently absorbed through the oral mucosa, especially with sublingual exposure. This efficient absorption system through the salivary route bypasses the first pass clearance by the liver and therefore results in greater BPA exposure than absorption from the gastrointestinal tract alone. However, this observation has not been confirmed in humans and therefore further studies are needed.
Free BPA in humans is rapidly metabolized by glucuronide conjugation or sulfonyl conjugation and then excreted through the kidneys. Physiological pharmacokinetic models suggest that renal tubular reabsorption of BPA conjugates contributes to the detection of serum BPA levels in humans, but the role of this pathway in renal injury has not been investigated.
Enterohepatic circulation and fat deposition also affect renal BPA clearance, which explains the difference between serum BPA assay values and those predicted by pharmacokinetic data. secondary metabolic pathways of BPA include oxidation of catechol to O-quinolone, which may cause oxidative stress and increase BPA toxicity.
4. Albuminuria
Albuminuria occurred after BPA exposure in 3055 adults living in Shanghai, China, the first study to document albuminuria after BPA exposure in healthy individuals. Regardless of whether BPA excretion was used as a continuous or categorical variable, the risk of small amounts of albuminuria (albuminuria/creatinine <30 mg/g) was higher in those with the highest estimated BPA exposure based on urinary excretion rates.
A study that included 710 children who participated in the NHANES 2009C2010 survey confirmed this correlation, finding a statistically significant higher urinary albumin/creatinine ratio of 0.91 mg/g in children in the highest quartile of urinary BPA levels. the effect of BPA on albuminuria was similar to that of phthalates.
No correlation between BPA exposure and microalbuminuria or macroalbuminuria was observed in either pediatric or adult studies. However, a study that included 534 children aged 6-10 years randomized to receive either BPA-free or BPA-containing resin material dental restorative treatment found no difference in the excretion rates of either albumin or N-acetyl-β-D-aminoglucosidase (both indicators of renal damage) between the two. BPA exposure associated with dental restorative materials or prophylactic dental sealants was less important in determining the outcome of renal damage caused by BPA than dietary intake of BPA.
Administration of BPA 50 mg/kg/day for 5 weeks to mice induced albuminuria and podocyte damage. Although the exact cause of albuminuria due to BPA is unclear and may be due to oxidative stress-induced endothelial dysfunction, these data suggest that BPA has adverse effects on glomeruli. Exposure of podocytes to low (10 nM) or high (100 nM) concentrations of BPA in vitro promoted cellular hypertrophy, decreased cell viability, induced apoptosis, and reduced podocin and nephrin expression.
6. eGFR
A study evaluated the effects of BPA exposure on renal function. In 2573 patients included in the NHANES
2003C2006 survey of adults without kidney disease, urinary BPA and trichlorophenoxychlorophenol (a synthetic antimicrobial agent found in many household products, including antimicrobial hand sanitizers) excretion was found to decrease with lower GFR. GFR was estimated using the CKD-EPI formula and BPA excretion was found to be independent of GFR.
6. Blood pressure
One study included 239 adults (mean age 52 years) and found an increased risk of hypertension and diabetes associated with urinary BPA excretion <0.85 >0.85 μg/l. A study including 560 non-welfare facility adults aged ≥60 years similarly showed a 1.2 advantage ratio for systolic BP >140 mmHg or diastolic BP >90 mmHg in those with fourth quartile urinary BPA excretion rates versus first quartile urinary BPA excretion rates. similarly, a study including 1,380 adults participating in the NHANES 2003C2004 survey showed that high urinary BPA excretion levels were associated with the development of hypertension (blood pressure >140/90 mmHg). After adjusting for multivariates, the dominance ratio of the third group (BPA >4.0ng/ml) to the first group (BPA <1.5ng/ml) was 1.5.
A small cohort study that included obese children aged 3-8 years showed that BPA exposure was associated with elevated diastolic blood pressure. A follow-on crossover study that included 60 Korean adults showed that drinkers of soymilk from a cup had 4-5 mmHg higher blood pressure and significantly higher urinary BPA excretion 2 hours later than drinkers of soymilk from a glass.The effect of BPA on blood pressure has prompted researchers to conduct longitudinal studies to examine cardiovascular outcomes. A prospective European cancer study (Norfolk Study) initiated in the United Kingdom included 758 subjects aged 40-74 years with no prior history of cardiovascular disease. 10-year follow-up results found an increased risk of coronary heart disease in those with high BPA at the time of inclusion compared to those with low BPA at the time of inclusion in the study. Specifically, for each standard deviation increase in urinary BPA (4.56 ng/ml), the advantage ratio OR for the development of coronary heart disease was 1.13. Subgroup analysis of this cohort study included 745 study subjects and found that BPA exposure was associated with an increased likelihood of developing clinically detectable peripheral arterial disease.
The Prospective Investigation of the Vasculature in the Elderly in Uppsala study (PIVUS study) included 1,016 study subjects aged 70 years and found that coronary risk was not associated with serum BPA levels according to the Framingham risk score. And other studies using the NHANES database failed to confirm an association between BPA exposure and cardiovascular outcomes. Therefore, the investigators questioned the validity of the conclusions of the NHANES cross-sectional analysis regarding the effects of short-term environmental chemical exposure on chronic complex diseases.
II. Perfluoric acid
1. Contaminants
(PFAA) is a synthetic organofluorine compound in which all hydrogen atoms in the hydrocarbon backbone are replaced with fluorine. This chemical structure is highly stable and heat resistant (Table 2, Supplementary Figure 1d). potential precursor compounds for PFAA are derived from 2 main technologies: electrochemical fluorination reactions (fluorinated organofluorine compounds preparation methods) and polymerization reactions (free radical polymerization reactions).
These two reaction processes are used in the production of various professional surface retaliators, sealants and surfactants.PFAA is widely used in carpet and upholstery antifouling sprays, fire fighting foams, nonstick pan surfaces and food packaging.
National Biomonitoring Surveys show that PFAA is detectable in the blood of over 98% of Americans (age 12-60+). serum PFAA levels are highest in men, age 40+ and high BMI populations in the Daegu, Korea population, which is similar to BPA. Unlike BPA, serum PFAA levels were directly related to socioeconomic status, with a relatively low PFAA burden in high-income populations. Differences in food procurement patterns among populations with different incomes may indicate changes in the correlation between socioeconomic status and environmental chemical exposure.
Both perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are 8-carbon alkyl compounds that have been widely used for decades. In the United States, PFOS was phased out of the market in 2012, while long-chain PFAA was withdrawn from the market in 2015. Long-chain PFAA has a half-life of 7-15 years, so the effects of previous exposure to long-chain PFAA remain relevant. Short-chain PFAAs have short half-lives, and short-chain PFAAs such as perfluoric acid (PFHxA) and perfluorononanoic acid (PFNA) have also been circulating in the environment and may also contribute to short- and long-term health concerns. Compared with participants in the NHANES
1999C2000 survey, compared to study subjects participating in the NHANES
2003C2004 survey subjects had consistently increased PFNA concentrations detected in serum. Perfluorosulfonic acid (PFHxS), the main metabolite of PFHxA, remained stable in the NHANES 2009C2010 and
2007C2008 survey studies remained stable.
A Swedish study of trends in serum PFAA concentrations from 1996 to 2010 showed a 4.3% annual increase in PFHxS and an 11% annual increase in perfluoroalkyl butane sulfonic acid (PFBS), a short half-life metabolite of 4-carbon PFAA, which is increasingly used as a substitute for PFOS in foods. is likely to be a persistent health problem.
2. Metabolism
PFAA is subject to significant bioaccumulation in the brain, liver, lungs, bones, and kidneys. PFAA is exceptionally stable to metabolic and environmental degradation due to carbon-fluorine binding. The persistence of human serum PFAA over time may reflect the combined effects of end-product release substances, materials used in the manufacturing process, and environmental and metabolic degradation of precursor compounds.
The persistence of PFAA throughout its half-life in humans and animals is well understood, but its toxicity profile and mechanisms of persistence are not fully clarified.PFAA is excreted primarily through the kidneys in a very slow, concentration-dependent manner.The carbon chain length of PFAA affects its pharmacokinetic profile, and small molecules of PFAA are more readily cleared by the kidneys than large molecules of PFAA.PFAA is more readily cleared by the kidneys in different The differences between species and sex may reflect differences in organic anion transport protein expression and putative renal tubular reabsorption.
Low levels of PFAA can persist in tissues for long periods of time. A study that included 26 adults retired from fluoridation studies with no other occupational exposure to PFAA showed
The geometric clearance half-lives of serum PFAA were as follows: 4.8 years for PFOS, 7.3 years for perfluorooctyl sulfate (PFHS), and 3.5 years for PFOA. Although studies on PFAA are increasing, there is still a huge gap in the understanding of the pharmacology and toxicity of these compounds. Recognition of PFAA pharmacology and toxicity is important to evaluate their risk (Table 1).
3. eGFR
The strength of the relationship between PFAA exposure and impaired renal function is not as strong as some of the other organic pollutants discussed in this review. However, the available studies do surface that PFAA has adverse effects on renal function and more studies are needed to explore this issue (Table 5).
One study included 4587 adults who were also NHANES 1999C2000 and
2003C2008 survey study subjects. The risk of chronic kidney disease was found to be higher in the group with the highest PFOA or PFOS levels (>5.9 ng/ml) than in the group with the lowest PFOA or PFOS
levels (<2.8 ng/ml) were 1.7 and 1.82 times higher than those in the lowest group.
Studies in children have also confirmed the considerable adverse effects of PFAA exposure on the kidneys. One study included 9,600
A cross-sectional analysis has found a 0.75 ml/min/1.73 m2 decrease in eGFR for each quartile spacing increase in serum PFOA concentration.
and PFHxS measurements were associated with reduced eGFR, but serum PFOA concentrations predicted at enrollment were not statistically correlated with GFR. The correlation between serum PFAA concentrations and GFR may be a consequence rather than a cause of reduced renal function, and these study data increase this possibility.
A longitudinal study of PFAA exposure included people living near hazardous waste as study subjects and did not find an effect of PFAA on GFR when analyzed according to residential address and distance from the waste. Finally, a study with a population from the NHANES 2003C2010 survey, which included 1961 adolescents aged 12-19 years, found that eGFR was 6.6C9.5 ml/min/1.73 m2 lower in the group with the highest PFOA and PFOS excretion rates than in the group with the lowest excretion rates.
4. Blood pressure
Preclinical data have linked descending PFAA exposure to vascular injury and hypertension. However, a study using children from the NHANES 1999C2000 and 2003C2008 surveys, which included 1665 children, did not find an association between serum PFOA and PFOS concentrations and hypertension (systolic and or diastolic blood pressure >95% percentile) (Table 4).
5. uric acid concentrations
Serum PFOA and PFOS levels were positively associated with hyperuricemia in adults (Table 6). data from adults in the NHANES 1999C2000 and 2003C2008 surveys showed that the multivariable-adjusted dominance ratio OR for hyperuricemia (uric acidacid ≥ 357 μmol/l [≥6 mg/dl]) in the highest quartile group of serum PFOA and PFOS levels was 1.97. Data from 1772 children investigated in NHANES 1999C2000 and 2003C2008 also showed the same correlation between serum PFOA and PFOS levels and hyperuricemia, with a multivariable-adjusted OR of 1.62 for hyperuricemia.The NHANES 2003C2010 study included 1961 children aged 12-19 years. The results found that serum uric acid concentrations were 12 μmol/l (0.20 mg/dl) higher in the group with the highest quartile of serum PFAA levels than in the group with the lowest quartile of serum PFAA levels, and the results were statistically significant.