Age- and sex-stratified serum reference intervals for eight trace elements in a large Japanese screening cohort

Population-specific, age- and sex-stratified reference intervals (RIs) for many serum trace elements remain limited, constraining the clinical interpretation of inductively coupled plasma mass spectrometry (ICP-MS)-based measurements.

To derive age- and sex-stratified serum reference intervals-not previously available for a large Japanese screening cohort-for eight trace elements (Co, As, Se, Rb, Sr, Mo, Ag, and Cs), and to assess between-facility and between-year variation.

A predefined 17-element panel was measured by ICP-MS in adults participating in an optional screening initiative at 12 sites in Japan (2017-2020). After age and eligibility exclusions, deduplication to one sample per participant, and removal of two sites with fewer than 20 participants, 17,523 individuals from 10 sites were retained for analysis. From the 17-element panel, the eight target analytes were pre-specified for RI derivation. RIs were estimated using a CLSI EP28-A3c-oriented statistical framework with Box-Cox transformation and bootstrap 90% confidence intervals. Pooling decisions were guided by Kruskal-Wallis effect sizes and RI width ratios.

All eight elements showed age- and/or sex-related variation. As and Mo were generally higher in older age groups in both sexes, and Ag and Cs also tended to be higher in older groups (non-monotonic patterns), whereas Rb was generally lower in older groups. Se was relatively stable in men but increased up to the 60-69-year age group in women. Co was higher in women than in men, with a higher upper reference limit at ages 20-49. Sr upper reference limits generally increased with age in both sexes, especially in women aged ≥70 years. Between-year and between-site effect sizes were small overall, supporting pooled RI construction.

This study provides large-scale, age-decade- and sex-stratified descriptive serum RIs for eight trace elements that previously lacked established Japanese reference intervals. These intervals support contextual interpretation of ICP-MS biomonitoring data.

This study provides large-scale, age-decade- and sex-stratified, descriptive serum concentration intervals for eight trace elements that lack established age- and sex-stratified serum reference intervals for Japanese adults (Co, As, Se, Rb, Sr, Mo, Ag, Cs). Derived from a multicentre screening population rather than a formally defined healthy cohort, these descriptive intervals support the contextual interpretation of ICP-MS-based biomonitoring data and provide a basis for future toxicological and nutritional assessments.