Association of exposure to synthetic phenols and metal(loid)s with early puberty in Spanish girls: a multicentric case–control study

Olivas-Martinez and colleagues measured eight metal(loid)s and synthetic phenols in first morning urine from girls recruited in six Spanish hospitals during 2018–2022. Higher urinary zinc was associated with greater odds of early puberty and precocious puberty in adjusted models, while the continuous models for arsenic, copper, mercury and nickel did not identify statistically significant associations. The combined chemical mixture was associated with early puberty, with bisphenol A contributing the largest positive weight. This is human biomonitoring and observational health evidence; no sunscreen, fish, food or other consumer product was sampled.

Key numbers

There were 310 participants: 182 cases and 128 controls. Cases comprised 101 girls with precocious puberty, 74 with premature thelarche, six with early pubarche and one with isolated vaginal bleeding. Metal measurements were available for 180 cases and 127 controls; synthetic phenol measurements were available for 181 cases and 126 controls. Mean ages were 7.44 years (SD 0.78) and 6.24 years (SD 1.28), respectively. Recruitment occurred during 2018–2022; the paper provides no per-year or per-region metal concentration estimates (PDF pp. 1–4, Table 1; p. 5, Table 2).

The following are urine concentrations in the paper’s native unit, ng/mL, not concentrations in a consumer product. Methods describes measuring specific gravity for dilution adjustment, but Table 2 does not explicitly label its medians as adjusted or unadjusted. Specific-gravity medians were 1.024 in cases and 1.023 in controls. Each metal row uses 180 cases and 127 controls (PDF p. 5, Table 2).

The table footnote specifies a Mann–Whitney test for chemicals detected in more than 85% of samples and a chi-squared comparison of detected versus undetected categories for chemicals detected in fewer than 85%. Therefore, the reported p-values for cadmium (Cd), Mn and lead (Pb) should not be presented as median-comparison tests. The Mn median is censored below 0.07 ng/mL; it is not zero. The main PDF does not report a complete table of metal LODs or LOQs.

Continuous-exposure models included arsenic (As), Cu, mercury (Hg), nickel (Ni) and Zn because their detection frequencies exceeded 85%. Odds ratios below are per two-fold increase in urinary concentration; adjusted models include age, hospital and maternal education (PDF p. 3, Methods; p. 6, Table 3).

Zinc in the third versus first tertile was associated with an OR of 2.28 (95% CI 1.10–4.73) for all early-puberty diagnoses. The authors also reported inverse associations for categorized Cd and Cu exposures. Figure 1 has no numeric labels for these estimates, so their exact odds ratios and confidence intervals are not reconstructed from plot positions. These observations do not demonstrate a protective effect of cadmium or copper (PDF p. 6, Results; p. 7, Figure 1).

BPA medians were 1.78 ng/mL in cases and 0.60 ng/mL in controls. Its adjusted OR per doubling was 1.44 (95% CI 1.19–1.73) for all diagnoses, 1.29 (1.05–1.58) for premature thelarche and 1.69 (1.26–2.27) for precocious puberty. This phenol context matters when interpreting results for the joint mixture (PDF pp. 5–6, Tables 2–3).

The mixture contained BPA, methylparaben, benzophenone-3, As, Cu, Hg, Ni and Zn. Effects below are per one-quartile increase in joint mixture concentration, adjusted for age, hospital and maternal education (PDF p. 7, Table 4).

BPA’s reported positive-direction mixture weights were 46% for all diagnoses and 52% for precocious puberty. A model weight is not the proportion of cases caused by that chemical, and the joint estimate cannot be attributed to metal exposure alone (PDF p. 6, Results; p. 8, Figure 2).

Methods (brief)

This was a multicentric hospital-based case–control study. Participants collected a single first morning void urine sample in a polypropylene container. Samples remained frozen at −80 °C before analysis at the University of Granada. Metals were measured using an Agilent 8900 triple quadrupole inductively coupled plasma mass spectrometer. Synthetic phenols were measured by dispersive liquid–liquid microextraction and ultra-high performance liquid chromatography with tandem mass spectrometry. Specific gravity was measured with a handheld refractometer to address urine dilution. The main paper refers sample preparation and analytical quality control to supplementary material (PDF pp. 2–3).

Values below the LOD were assigned LOD/√2 for analysis. Biomarkers with detection frequencies above 85% entered log-transformed and tertile models; those detected in 50–85% entered categories based on the LOD and median; those detected in fewer than 50% entered detected/undetected models. Quantile g-computation used quartiles of eight frequently detected chemicals and 1,000 bootstraps. Primary confounder adjustment comprised age, hospital and maternal schooling. Sensitivity analyses added BMI or excluded girls from the hospital without controls (PDF p. 3).

The absence of controls at HUVA, unequal case/control ages, one urine measurement, residual confounding and multiple comparisons limit interpretation. The authors also identify urine as an unsuitable measure of chronic Pb and Hg exposure, potentially causing exposure misclassification. They report similar sensitivity-analysis results, but the detailed supplementary estimates were not available in the main PDF (PDF pp. 6, 8–9).

Implications

The study supports source-native urinary medians, detection frequencies and associations with contemporaneous pubertal diagnoses. It is an exposure and health-effect source (lane a4), with urine as its matrix and Spain as its population jurisdiction. Product and ingredient arrays are empty because a research-pull query mentioning sunscreen does not establish a measured product or an exposure source.

The case–control design and a single urine sample cannot establish exposure before puberty onset or a causal effect. Arsenic and mercury were measured without reported speciation: their results are retained as total/unspeciated elemental measurements, not inorganic arsenic or methylmercury. The values cannot supply product contamination concentrations, ingredient contamination profiles, product-specific exposure attribution or clinical risk thresholds. Detailed analytical quality-control information and several sensitivity analyses are delegated to a supplement absent from the preserved main PDF.

This source contributes urinary exposure and reproductive-health context to the relevant metal pages. It separates individual-metal associations from a mixture signal driven primarily by BPA, and keeps negative or inconclusive findings visible alongside the zinc association. It neither identifies the products responsible for exposure nor supports individual clinical predictions.

The source was located under a sunscreen query, but its actual participants and laboratory matrix govern routing. The prior fish and mineral-sunscreen routes were unsupported and should not contribute to product occurrence evidence. No regional concentration gradient, historical exposure trend or remediation effect was measured.

Related evidence

• Arsenic
• Cadmium
• Copper
• Mercury
• Manganese
• Nickel
• Lead
• Zinc

Update history

The five most recent substantive edits to this page, classified major (evidence or structure moved), correction (a published value or statement was wrong and has been fixed), or minor (narrative rewritten without changing the underlying evidence). Each description is derived from what the edit did to this page; the linked commit is the authoritative record, routine regeneration passes are excluded, and the full version history lives in git.