Environmental context related to hydrogen sulphide and regional variation in utilisation of ROCK inhibitors in Japan: a nationwide ecological analysis

Abstract

Abstract Regional variation in healthcare utilisation is widely documented, yet the contribution of natural environmental context to prescribing patterns remains poorly understood. Geological environments shape long-term background exposure to naturally occurring substances, but population-level evidence linking geological context to ophthalmic prescribing is limited. Experimental studies have suggested that hydrogen sulphide (H 2 S) may interact with the RhoA/Rho kinase (ROCK) signalling pathway, which is the pharmacological target of ROCK inhibitor medications used for glaucoma. We conducted a nationwide ecological cross-sectional study using prefecture-level data from all 47 prefectures of Japan. Annual per-capita prescription volumes of ripasudil ophthalmic solution were obtained from the National Database of Health Insurance Claims, and geological context was quantified using the volcanic rock area ratio (VRAR) as a geological background indicator reflecting long-term environmental context, including potential exposure to H 2 S, rather than a direct measure of exposure. Associations were analysed using locally estimated scatterplot smoothing (LOESS), multiple linear regression, and random forest modelling with adjustment for demographic and healthcare-related covariates. Ophthalmic prescribing patterns showed marked regional variation across Japan, and analyses identified a consistent non-linear association between geological context and per-capita ROCK inhibitor prescriptions, with prescription levels peaking in prefectures with intermediate VRARs. Multivariable linear regression showed limited explanatory power, whereas random forest models suggested that geological context was among the most influential predictors among the examined variables. These findings suggest that regional geological context may represent a previously underexplored structural factor associated with variation in ophthalmic prescribing patterns, highlighting a potential intersection between environmental context and population-level pharmacological utilisation.