Skin lesions associated with chronic exposure to arsenic in drinking water in rural Western Iran

Abstract

Chronic exposure to arsenic through drinking water is a major public health concern and is associated with a wide range of adverse health effects, including dermatological lesions, cardiovascular disorders, and increased cancer risk. In this cross-sectional study, the prevalence of arsenic-related skin problems, i.e., hyperpigmentation and keratosis, in relation to arsenic level in drinking water in rural regions in northwest Hamadan Province, Iran, was investigated. Arsenic levels in drinking water during 2022–2023 were obtained from the Hamadan University of Medical Sciences Health Department. Three villages with arsenic levels above 50 µg/L in Kabudarahang County were selected as exposure sites, and two villages with low arsenic levels (< 2 µg/L) were selected as controls. 189 individuals from the exposed village residents and 223 from control village residents were interviewed with medical screenings. Demographic and health-related variables, including age, BMI, blood pressure, and skin lesion history, were recorded. Skin symptoms were significantly more prevalent among the exposure group: keratosis (adjusted OR = 10.18, 95% CI: 1.28–80.75, p = 0.028), hyperpigmentation (adjusted OR  3.94, 95% CI 1.05–14.67, p = 0.041), and other cutaneous complications (adjusted OR 5.05, 95% CI 1.66–15.33, p = 0.004). Age was a risk factor per se with each additional year having a 2–4% increased risk of skin lesions. Systolic blood pressure differed between groups (p < 0.001), suggesting possible interactions with cutaneous manifestations. Arsenic in drinking water at high levels has strong association with elevated prevalence of skin lesions, and therefore a requirement for systematic waters monitoring and mitigation processes.

Introduction

Arsenic is widely distributed in the Earth’s crust and is the twentieth most abundant naturally occurring element. It exists in both inorganic and organic forms, each with distinct valence states and environmental behaviors. Organic arsenic compounds—typically in pentavalent forms—are considerably less toxic because they are not readily taken up by cells and undergo limited metabolic transformation. In contrast, inorganic arsenic species such as trivalent arsenite (As III) and pentavalent arsenate (As V) are the most common and highly toxic forms present in groundwater^1,2.

Arsenic-contaminated groundwater is a major route of exposure for the majority of the population in arsenic-endemic regions of the world, including the USA, China, Chile, Bangladesh, Argentina, Iran, and India^3–5.

Iran is located within a geogenic arsenic belt extending from the northwest to the southwest of the country, where elevated arsenic concentrations in groundwater have been widely reported. Previous studies, including national systematic reviews and regional investigations, have documented high arsenic levels in multiple provinces such as West Azerbaijan (Takab), East Azerbaijan (Hashtroud), Kurdistan (Qorveh and Bijar), Ardabil, Kerman, Razavi Khorasan (Kashmar), Sistan and Baluchestan (Khash), and Fars (Maharloo). Reported mean groundwater arsenic concentrations in these regions range from approximately 39 µg/L in Ardabil Province to over 190 µg/L in Kurdistan Province, with values around 80 µg/L in parts of East Azerbaijan^6–8.

Although locally important anthropogenic sources do exist, most arsenic in Iranian aquifers arises from natural geological processes. Iron oxides, a by-product of weathering of metamorphic and volcanic rocks, act as sinks for arsenic through adsorption and co-precipitation. Under certain environmental conditions—e.g., elevated pH or redox state changes—arsenic is remobilized into the groundwater, particularly where high felsic volcanic rock concentrations occur⁹.

Based on epidemiological studies and because of arsenic’s extreme toxicity, the United States Environmental Protection Agency (USEPA) and the International Agency for Research on Cancer (IARC) have classified arsenic as a Group A, or human carcinogen. As a primary source of potable water, communities across the world are predominantly exposed to excessive amounts of arsenic through groundwater. Arsenic cannot be biodegraded and can be transformed into insoluble forms by reacting with elements like iron¹⁰. Trivalent inorganic arsenic (arsenite) is very toxic, which reacts with sulfhydryl groups of enzymes and proteins and damages cells by repeated oxidative reactions. Arsenite disrupts the metabolic function of over 200 vital enzymes. Arsenate, owing to its structural similarity with phosphorus, can replace phosphorus in compounds of phosphate, like bones¹¹. These metabolic compounds were associated with a greater risk of cancers, including skin, bladder, kidney, and liver cancers. The non-carcinogenic effects include skin lesions, vascular disorders, diabetes mellitus, and neurotoxicity¹². In most countries of the world, including Bangladesh and Pakistan, long-term exposure through drinking water has been recognized as a significant public health concern, and concentrations of arsenic have been reported at levels up to 450 µg/L. Earlier epidemiological studies have documented that arsenic intake by way of ingestion, inhalation, or dermal entry results in severe health issues, disproportionately affecting local people who rely on contaminated water¹³.

Cutaneous manifestations are hyperkeratosis, pigmented lesions, alopecia, and carcinomatous neoplasms¹⁴. Melanosis and palmoplantar keratosis are common, the chronic effects depending on duration of exposure, pathway, physicochemical characteristics of compounds, and targeted biological species¹⁵. World Health Organization (WHO) and US Environmental Protection Agency (US EPA) arsenic standard was lowered from 50 µg/L to 10 µg/L in 1993. Iran lowered its standard from 50 µg/L to 10 µg/L in 2010¹⁶. Studies by Tseng et al. identified that skin color changes (e.g., melanosis) and palmoplantar keratosis would typically appear after exposure of 5–15 years, whereas Kitchin’s study observed these changes within 5 years^17,18. One study published recently in Pakistan used the inclusion criterion of > 6 months’ duration of exposure to water with arsenic levels > 10 µg/L and reported that there was a good correlation between arsenic exposure and skin lesions¹⁹. Previous experience tells us that arsenical skin lesions are pre-cancerous conditions for cancers arising in other organs subsequentlyIn Iran, arsenic contamination has been detected in some provinces, including Hamadan. Historical cases of arsenic dermatitis, such as the 1986 Bijar County outbreak in Kurdistan Province, illustrate the risk of arsenic dermatitis²⁰. In a second study from East Azerbaijan Province, arsenic levels many times above standards and prevalence of hyperkeratosis and pigmentation considerably higher in contaminated villages²¹. Health Department of Hamadan University of Medical Sciences (UMSHA) information verifies groundwater arsenic pollution in Hamadan Province and significantly elevated concentrations in Kabudarahang County. Given the well-documented health risks associated with exposure to arsenic from contaminated water sources, this issue is of significant public health importance in the province.

This epidemiological investigation is the first study in Hamadan Province designed to investigate the association between the prevalence of skin lesions and high-arsenic-exposure villages compared with control, non-exposure villages.

Materials and methods

Study area

The survey was conducted in Kabudarahang County, Hamadan Province, Iran (35°11′40′′ N, 48°43′25′′ E), covering an area of 4,025 km² (≈ 20.5% of the province). It is, on average, 1,680 m above sea level, and groundwater is the primary source of drinking and irrigation water. Figure 1 illustrates the study area and spatial distribution of arsenic concentration in Hamadan province. The map was created using ArcMap 10.8 (Esri), and the spatial distribution of arsenic was generated by interpolating sampling point data using the Inverse Distance Weighting (IDW) method. Village exposure status was assigned based on the measured arsenic concentrations. Arsenic contamination of the region is geogenic, related to volcanic rocks and sulfide minerals²². Arsenic concentrations in water vary between 8 and 180 µg/L, which is in excess of the WHO standard of 10 µg/L. Arsenic concentration data were obtained from contemporaneous peer-reviewed studies conducted in the study area^23,24, as well as from routine and continuous groundwater monitoring programs carried out by the Health Department of Hamadan University of Medical Sciences. Given the public health significance of arsenic contamination, these measurements are performed regularly using standardized sampling procedures and validated analytical methods, and were used in the present study to classify village-level exposure. Five villages were selected on the basis of arsenic concentration: A and B (50–100 µg/L), C (> 100 µg/L) as exposed, and D and E (< 2 µg/L) as not exposed. Mean arsenic level was 62.33 µg/L in exposed and ≤ 2 µg/L in unexposed villages²⁴.

Fig. 1.

Study area and spatial distribution of arsenic concentration in Hamadan province. Map created by the authors using ArcMap 10.8 (Esri). Base geographic data were obtained from the National Cartographic Center (NCC) of Iran. Arsenic concentration data are based on field measurements and spatial interpolation (IDW method).

Study population

The study was approved by the Ethics Committee of Hamadan University of Medical Sciences (Approval No. IR.UMSHA.REC.1401.453). All procedures adhered to the ethical standards of the institutional and national research committees and the 1964 Declaration of Helsinki and its later amendments.

Participants in each village were selected through simple random sampling using household lists obtained from local health centers. A computerized random number generator was used to select eligible individuals, and no stratification was applied. A total of 451 residents aged 6–83 years from five villages were initially assessed. For participants under the age of 18, written informed consent was obtained from a parent and/or legal guardian in addition to the child’s assent where appropriate.

After excluding 39 tobacco users, 412 participants (189 exposed, 223 unexposed) were included in the final analysis. Additional exclusion criteria were malignancy, hepatitis, residence in the village for less than one year, alcohol use, and known occupational exposure to arsenic. Demographic characteristics, weight, height, hypertension status, sex, occupation, and duration of residence were collected using structured questionnaires. Blood pressure was measured by an experienced physician.

Skin manifestations

Two types of arsenic skin manifestations were screened for: keratosis and hyperpigmentation (including hypopigmentation). Hyperpigmentation refers to darkening of skin areas or nails due to increased melanin production, often appearing as dark spots or patches. For the purposes of this study, hyperpigmentation was diagnosed based on the presence of clearly demarcated dark-brown to black macular lesions on sun-exposed or non-exposed skin, excluding freckles, lentigines, or post-inflammatory hyperpigmentation with a known non-arsenic etiology. Hypopigmentation refers to lightening or depigmentation of skin areas due to reduced melanin, typically presenting as white spots or “raindrop” patterns. It was defined as discrete, rounded, or irregular pale-to-white macules resembling a “raindrop” pattern, primarily on the trunk or extremities. Keratosis refers to excessive keratin growth on the skin (produced by keratinocytes, the main epidermal cells), manifesting as small bumps typically on palms and soles, and occasionally on the backs of hands, feet, or limbs. In this study, keratosis was defined as palpable, rough, elevated lesions on palms or soles, ranging from punctate papules to larger plaques, in the absence of other common causes such as chronic friction, psoriasis, or fungal infection. Lesions were further classified as mild (scattered papules), moderate (multiple or confluent papules), or severe (thickened plaques with fissuring).

All diagnoses were made by a qualified dermatologist blinded to participants’ exposure status and corroborated by digital photographic review^25,26.

Procedures for field data collection

Demographics, weight, height, hypertension status, gender, occupation, and duration of residency were collected using a structured questionnaire containing standard epidemiological items, administered via face-to-face interviews by trained researchers. Smoking status was assessed through self-report during these interviews. Although biochemical validation was not performed, interviewers followed standardized protocols to minimize reporting bias. Objective measurements (weight, height, blood pressure) were verified by a physician. The content validity of these routinely used items is well-established through their consistent application in prior epidemiological studies, with no major reliability concerns reported in the literature.

Clinical examinations were conducted by a qualified physician who accompanied the interviewer to health centers in the study villages. Individuals suspected of having arsenic-related dermatological conditions underwent additional medical examination. Before the physician’s consultation, the interviewer recorded demographic and health-related characteristics using face-to-face interviews. Subsequently, participants were asked whether they consented to a dermatological examination by a physician affiliated with the Kabudarahang Health Department. During the skin examination, the dermatologist was blinded to participant information. To control for observation bias, the interviewer took digital photographs of the participants’ skin findings. These photographs were later evaluated after the clinical examinations to confirm diagnostic accuracy. Results from the dermatological examination were systematically recorded as binary variables (yes/no) for the following conditions: hyperpigmentation, keratosis, and other skin complications.

Arsenic determination in drinking water

Concentrations of arsenic in drinking water were obtained from two sources: (1) official records provided by the UMSHA Health Department, following standard environmental monitoring procedures, and (2) confirmatory sampling and analysis conducted by the research team during the study period, as reported in a previous study²⁷. Water samples from the public supply system were collected systematically at all sampling points using pre-washed, acid-washed polyethylene bottles to prevent contamination and ensure analytical accuracy²⁸. After collection, samples were tightly wrapped with parafilm, labeled, and refrigerated immediately on-site to preserve integrity.

Samples were analyzed using inductively coupled plasma mass spectrometry (ICP-MS). Quality assurance procedures included the use of certified reference materials (ERM^®-CA011b for trace elements in water), procedural blanks with each batch, and triplicate measurements of every tenth sample to assess precision. Calibration standards were prepared fresh daily from certified stock solutions, and a continuing calibration verification standard was analyzed after every 10 samples to ensure instrumental stability (recovery: 95–105%). The method detection limit (MDL) was determined as 3× the standard deviation of seven replicate blank measurements and confirmed to be 1 µg/L for arsenic. Further details on analytical techniques and quality assurance are provided in our previously published article²⁹.

Exposure classification based on arsenic levels

Village exposure status (exposed vs. unexposed) was assigned based on the consistency between the two data sources described above, with priority given to direct measurements taken concurrently with the health survey. This approach ensured that exposure classification reflected both historical data and current conditions during the study period.

Statistical analysis

Continuous variables were expressed as mean ± SD, and categorical variables as frequencies and percentages. Independent t-tests or Mann–Whitney U tests were used to compare continuous variables, and chi-square or Fisher’s exact tests were applied for categorical comparisons. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the associations between arsenic exposure and skin manifestations.

Before constructing the multivariable logistic regression models, all candidate variables were assessed for multicollinearity. Variables were selected for inclusion based on (1) conceptual relevance reported in previous literature (e.g., age, sex), and (2) a p-value < 0.20 in univariable analyzes. The final adjusted model included age, sex, occupation, and duration of residence as covariates. Multivariable logistic regression models were fitted separately for keratosis and hyperpigmentation. All analyzes were conducted using Stata version 18 and Excel 2021, and statistical significance was defined as p < 0.05.

Results

Characteristics of study population

We recruited 189 individuals living 3 villages with high arsenic in drinking water to participate in this study. 223 individuals were selected as the control group with low arsenic in drinking water. The main characteristics of study population, based on the criteria defined in Sect. 2.1, was shown in Table 1. 39 individuals were excluded due to current or past smoking. A significant difference was observed between the groups across several demographic variables. Mean (± SD) age and body mass index (BMI) in the exposed group were 51.57 ± 18.19 years and 24.43 ± 4.8 kg/m², respectively. More than 60% of participants in exposed groups were female. While unexposed individuals were approximately the same in males and females. For the unexposed group, mean age, BMI were 33.91 ± 21.74 years, 22.81 ± 3.6 kg/m², respectively. Conversely, 43.94% of the unexposed group were aged 10–29 years, while only 5.29% in the exposed group fell within this age range (p < 0.001). Malnourished subjects, i.e. ≤18.5, was 7.9% and 14.34% in expose and unexposed group, respectively. We observed statistically significant differences between the two groups in terms of sex, age, hypertension, systolic blood pressure (SBP), BMI, and occupation status. The exposed group had a higher mean systolic blood pressure (116.23 mmHg ± 17.71) than the unexposed group (106.58 mmHg ± 13.68) (p < 0.001). The exposed group also exhibited a higher mean diastolic blood pressure (68.32 mmHg ± 26.36) compared to the unexposed group (64.52 mmHg ± 21.32) (p = 0.063). When age subgroups were evaluated, the number of subjects aged 60 years was higher in the exposed group than in the unexposed group. The residential duration of individuals in the study area in the exposed group was not significantly longer than the unexposed group. As seen in Table 1, 80% of both groups lived in the study area for more than 10 years. Predominant type of occupation in both groups was housewife and farmer/ rancher.

Table 1.

General characteristics of exposed and unexposed groups.

Demographic information	Exposed group (n = 189)	Unexposed group* (n = 223)	p- value
Sex [n (%)]
Male	64 (33.87)	116 (52.02)
Female	125 (66.30)	107 (47.98)
			0.000
Age[year, mean (± SD)]	51.57 ± 18.19	33.91 ± 21.74
			0.000
Age, year [n (%)]
10	4 (2.11)	21 (9.41)
10–29	17 (8.99)	98 (43.94)
30–59	95 (50.26)	59 (26.45)
60	73 (38.62)	45 (20.17)
			0.000
Residence time [year, n (%)]
1–10	44 (23.28)	37 (16.59)
10	145 (76.72)	186 (83.40)
			0.421
Hypertension [n (%)] **	23 (12.16)	11 (4.93)
			0.008
Blood pressure [mmHg, mean (± SD)]
SBP***	116.23 ± 17.71	106.58 ± 13.68
			0.000
DBP***	68.32 ± 26.36	64.52 ± 21.32
			0.063
BMI [mean (± SD)]	24.43 ± 4.8	22.81 ± 3.6
			0.003
BMI (kg/m2) [n (%)]
18.5	15 (7.93)	32 (14.34)
18.5–24.9	96 (50.79)	123 (55.15)
25-29.9	62 (32.80)	51 (22.86)
30	16 (8.46)	17 (7.62)
			0.045
Occupation status [n (%)]
Farmer & rancher	49 (25.93)	47 (21.07)
Housewife	122 (64.45)	84 (37.66)
Student	8 (4.24)	57 (25.56)
Service (labor, office)	8 (4.24)	33 (14.79)
Unemployment	2 (1.05)	2 (0.89)
			0.000

*Participants from villages with > 50 µg/L As, in drinking water.

**Hypertension were defined as self-reported antihypertensive medication use.

*** SBP: Systolic blood pressure/ DBP: Diastolic blood pressure.

Skin manifestations findings

The present study analyzed the association between arsenic exposure and the occurrence of skin diseases, more precisely hyperpigmentation and keratosis. The findings indicate that dermatological lesions were more prevalent among the exposed group, showing a strong association between arsenic exposure and the presence of these conditions. Figure 2a–c shows clinical photographs of typical manifestations, and Table 2 gives a summary of the relationship between sociodemographic factors chosen and the prevalence of skin lesions. Hyperpigmentation showed a strong association with arsenic exposure, with exposed participants exhibiting substantially higher odds of developing this condition compared with controls (OR = 3.94). Rising age was also a strong influence, with each additional year being linked with a modest but steady increase in risk. The remaining variables of sex, body mass index (BMI), and hypertension history were not significantly related. Systolic blood pressure was inversely related to hyperpigmentation, a finding that suggests a more complex physiological relationship and warrants additional study. Keratosis was even more strongly associated with arsenic exposure, with exposed individuals showing markedly higher odds of having the condition (OR = 10.18). Age was again a strong predictor, with risk increasing consistently as age went up. Sex was also found to have an influence, as women were at more than three times the risk of keratosis compared to men. Higher BMI was also linked with higher risk, but blood pressure was not strongly associated in this case (Table 3).

Fig. 2.

Representative clinical manifestations of arsenic-induced skin lesions observed in patients: (a,b) keratosis; (c) hyperpigmentation.

Table 2.

Associations between selected sociodemographic factors and skin lesions.

Skin lesion	Parameter	N (%)	OR	95% CI	P-value
Hyperpigmentation	group		6.35	1.08–22.28	0.004
	Exposed	15 (83.33)
	Unexposed	3 (16.67)
	Age		1.03	1.01–1.05	0.006
	Sex		2.04	0.71–5.85	0.181
	Male	4 (22.22)
	Female	14 (77.78)
	BMI		1.04	0.94–1.15	0.370
	Hypertension		0.64	0.08-5.00	0.675
	No	17 (94.45)
	Yes	1 (5.55)
	Blood pressure
	SHTN		0.98	0.98–0.99	0.009
	DHTN		1.03	0.99–1.07	0.129
Keratosis	group		26.39	3.50-198.60	0.001
	Exposed	19 (90.47)
	Unexposed	2 (9.53)
	Age		1.04	1.02–1.06	0.000
	sex		3.42	1.13–10.37	0.002
	Male	5 (23.08)
	Female	16 (76.92)
	BMI		1.01	1.01–1.21	0.035
	Hypertension		0.543	0.07–4.18	0.558
	No	1 (4.76)
	Yes	20 (95.24)
	Blood pressure
	SHTN		0.98	0.97–0.99	0.002
	DHTN		104	099-1.09	0.076
Skin complication	group		8.38	2.86–24.55
	Exposed	25 (86.20)
	Unexposed	4 (13.80)
	Age		1.03	1.01–1.05	0.000
	Sex		2.54	1.06–6.11	0.036
	Male	7 (24.13)
	Female	22 (75.87)
	BMI		1.05	0.97–1.14	0.214
	Hypertension		0.37	0.05–2.88	0.349
	No	28 (96.56)
	Yes	1 (3.44)
	Blood pressure
	SHTN		0.98	0.98–0.99	0.009
	DHTN		1.03	0.99–1.07	0.129

Table 3.

Adjusted odds ratios for skin lesions by category of arsenic exposure.

Skin lesion	Parameter	OR	95% CI	P-value
Hyperpigmentation	Group*	3.94	1.05–14.67	0.041
	Age	1.02	0.99–1.04	0.126
	Sex	1.98	0.64–6.12	0.231
	BMI	0.97	0.85–1.10	0.666
	SBP	0.98	0.96–1.00	0.150
Keratosis	Group	10.18	1.28–80.75	0.028
	Age	1.04	1.01–1.07	0.003
	Sex	2.16	0.64–7.35	0.214
	BMI	1.01	0.90–1.41	0.799
	SBP	0.98	0.97–0.99	0.10
Skin complication	Group	5.05	1.66–15.33	0.004
	Age	1.02	1.05–1.06	0.011
	Sex	2.11	0.848–5.271	1.08
	BMI	0.017	0.721–0.854	1.77
	SBP**	0.97	0.96–1.00	0.12

*Exposed and unexposed groups.

**Systolic blood pressure.

Along with these two principal conditions, a number of other dermatological disorders—acne, eczema, psoriasis, and infections—were also substantially more common in the exposed group, with risk in excess of eight times that of the control group. As previously, age and female gender were strongly predictive, and BMI and history of hypertension were not relevant. The aberrant inverse relationship with systolic blood pressure was again seen, suggesting that this variable is involved in some as-yet unforeseen way. Upon application of multivariate logistic regression models, group status (exposed vs. unexposed) remained a significant predictor of hyperpigmentation, keratosis, and overall skin complications after adjusting for other factors (Table 3). Age also continued to be significantly related to keratosis and overall complications, with each advancing year adding to the risk. Conversely, sex, BMI, and systolic blood pressure did not attain statistical significance consistently after adjusting. Together, these findings indicate that arsenic exposure and age are the most widespread and influential forces underlying the prevalence of skin lesions in this population. Other variables may contribute in more limited or situation-specific ways, but the overriding impact of arsenic exposure indicates the need for continued public health surveillance and further investigation of its dermatological consequences.

Discussion

Our findings demonstrate a strong association consistent with a dose-response relationship between arsenic exposure and dermatological lesions. The odds of hyperpigmentation were nearly four times higher (OR = 3.94, 95% CI: 1.05–14.67), and the odds of keratosis were more than ten times higher (OR = 10.18, 95% CI: 1.28–80.75) in the exposed compared to the unexposed group (Table 3).

These results align with and extend the robust evidence from other arsenic-endemic regions. Studies in northwest Iran, South Asia, China, and Bihar, India, have consistently reported a strong link between chronic arsenic exposure via drinking water and a heightened prevalence of these characteristic skin lesions^3–5,30.

This cross-regional consistency supports the generalizability of the arsenic-dermatotoxicity association and underscores its significance as a widespread public health concern.

Women in our study also showed a higher prevalence of keratosis and related complications, an observation that should be interpreted with caution. Several explanations are possible, including biological differences in skin characteristics, hormonal influences, or socio-behavioral factors such as greater domestic water use or more frequent contact with groundwater due to household responsibilities. For example, experimental evidence suggests a biological basis for sex-based differences in arsenic toxicity. Studies in animal models indicate that males and females metabolize arsenic differently, with variations in key metabolites like MMA and DMA and in the expression of the arsenic-methylating enzyme As3MT, which may influence susceptibility to toxic effects³¹.

However, because these behavioral and exposure pathways were not directly measured, these explanations remain speculative. Detailed exposure-behavior data would be needed to determine whether gender-specific patterns truly exist.

Our findings are consistent with reports from other arsenic-endemic regions. For example, a cross-sectional study from Bangladesh found significantly higher rates of melanosis and keratosis among women, suggesting a potential gender disparity in susceptibility or exposure patterns³². While such observations hint at meaningful sex-related differences, the mechanisms remain unclear, and further research is required to clarify whether these differences stem from biological susceptibility, sociocultural roles, or differential exposure opportunities.

As documented in prior research and supported by the findings of the present study, chronic oral exposure to inorganic arsenic is strongly associated with characteristic cutaneous manifestations, most notably melanosis and keratosis. Melanosis encompasses a spectrum of pigmentary alterations—including diffuse hyperpigmentation, spotted pigmentation, hypopigmented areas, and mixed ‘black and white’ macules—that typically appear on the trunk and extremities. The classic ‘rain-drop’ pattern of hypopigmentation is considered particularly indicative of chronic arsenic exposure. Keratosis appears later, mainly in the palms and soles with forms such as discrete, nodular, and spotted keratosis that at times occur together as spotted palmoplantar keratosis. All these skin lesions are important indicators of chronic arsenic exposure and toxicity³³.

An unexpected finding of this study was the inverse association between systolic blood pressure and certain skin lesions. This pattern should be interpreted with great caution, as it lacks a plausible biological mechanism and is more likely the result of residual confounding, age-related differences, or random statistical variation rather than a true physiological effect. Given the cross-sectional design and the possibility of multiple testing effects, this association may represent an artifact rather than a meaningful relationship. Future longitudinal studies with more detailed cardiovascular assessment would be needed to clarify whether this observation reflects a real underlying trend or is attributable to uncontrolled confounders.

BMI and a history of hypertension, however, did not have an effect on the risk of arsenic skin lesions significantly. This finding concurs with Bangladesh and West Bengal studies and suggests that metabolic and lifestyle risk factors play little role in comparison to the overriding influence of arsenic exposure itself¹³. A 150-study participant cross-sectional survey in Bihar, India, quantified daily arsenic exposure from water and food and correlation with hypertension risk. The survey reported a 40% hypertension rate but found no significant positive correlation between arsenic exposure and hypertension. Somewhat paradoxically, total arsenic exposure (Astotal) was associated with decreased overall hypertension risk consistent with evidence that higher arsenic exposure was associated with lower blood pressure. Additionally, there existed a weak inverse relationship between drinking water arsenic level and hypertension³⁴. In Zhao’s research, there was a positive and approximated non-linear relationship between arsenic exposure and the risk of hypertension but no noticeable correlation with diastolic blood pressure³⁵. Chen et al. investigated the relationship between early childhood, childhood, and adolescent arsenic exposure and adolescent blood pressure. None of the indicators of arsenic exposure were found to have any significant association with diastolic blood pressure. Their work indicates that present and early childhood arsenic exposure are related to elevated adolescent blood pressure, which may be compounded by higher body mass index during adolescence³⁶. Overall, the dermatological observations of this study are consistent with global literature, reaffirming that keratosis and hyperpigmentation are commonly observed among populations chronically exposed to arsenic and have been reported in previous studies as early markers of potential systemic toxicities, including skin, bladder, liver, and kidney cancers. However, given the cross-sectional nature of this study, temporal relationships between arsenic exposure and skin outcomes cannot be established, and the associations observed should not be interpreted as causal.

The concurrence of our clinical findings with geological data confirms that Kabudarahang is only a part of a wide geogenic belt of arsenic, where the natural process, and not human activity, is responsible for groundwater contamination. This supports the imperative need for systematic quality monitoring of water, special health screening for early diagnosis of arsenic dermatological lesions, and safe alternative sources of drinking water supply. As the first epidemiological evidence of this kind in Hamadan Province, our study provides a crucial foundation for national reduction initiatives and local public health policy. Future studies should also try to examine genetic susceptibility and nutritional cofactors that may influence arsenic-induced health consequences on exposed populations.

The findings of this study reveal a strong association between arsenic exposure and skin lesions in rural Hamadan. While the cross-sectional design limits causal inference, the results underscore the need for public health intervention. Beyond clinical care, integrated strategies for sustainable water management—such as implementing advanced spatio-temporal monitoring frameworks^37,38—are essential to identify high-risk zones, guide the provision of alternative safe water, and integrate dermatological screening into primary healthcare. Future longitudinal studies with individual biomarkers are recommended to clarify exposure-outcome relationships.

Conclusion

The findings of this study reveal a strong and significant association between chronic exposure to arsenic in drinking water and a markedly higher prevalence of dermatological signs, particularly keratosis (adjusted OR = 10.18) and hyperpigmentation (adjusted OR = 3.94), in high-arsenic villages compared to control areas in Hamadan Province. While the cross-sectional design precludes causal inference, the strength of these associations, along with their anatomical distribution (e.g., palmoplantar keratosis) and consistency with established global patterns of arsenic toxicity, underscores a substantial public health concern in these rural communities.

These results highlight the urgent necessity for systematic and continuous monitoring of drinking water quality in arsenic-endemic regions of Iran, particularly in geogenically contaminated areas like Kabudarahang County. Furthermore, they underscore the importance of implementing preventive public health measures, including:

• Providing access to alternative safe water sources for affected villages.

• Integrating early dermatological screening for arsenic-related skin lesions into primary healthcare services.

• Launching community-based education programs on the health risks of arsenic and the importance of using safe water.

As the first epidemiological study of its kind in Hamadan Province, this work provides a crucial evidence base for informing local public health policy and guiding national mitigation strategies. Future research should prioritize longitudinal studies with individual-level exposure biomarkers to better elucidate the temporal relationship and dose-response dynamics, as well as investigate the potential roles of genetic susceptibility and nutritional factors in modifying arsenic-related health outcomes.

Limitations of the study

This study has several important limitations that should be considered when interpreting the findings. First, the cross-sectional design precludes establishing temporal relationships and therefore does not allow causal inference between arsenic exposure and skin lesions.

Second, exposure assessment was based on village-level arsenic concentrations in drinking water rather than individual-level biomarkers. Although this approach is commonly used in community-based studies and measurements were validated through repeated sampling, it may have led to exposure misclassification and did not capture inter-individual variability related to water consumption, diet, metabolism, or duration of exposure.

Third, the exposed group was significantly older than the control group. Despite statistical adjustment for age, residual confounding cannot be ruled out. In addition, the study was limited to five villages, and no formal matching on socioeconomic status, nutritional factors, or healthcare access was possible, which may have influenced the observed associations.

Fourth, some odds ratios were accompanied by wide confidence intervals, reflecting limited statistical precision due to the moderate sample size and small numbers of cases in certain subgroups.

Finally, although smokers and individuals with known occupational exposure were excluded, other potential confounders—including genetic susceptibility, nutritional status, dietary habits, sunlight exposure, and additional environmental or occupational sources of arsenic—were not fully assessed.

Overall, these limitations indicate that the findings should be interpreted cautiously. Nevertheless, the study provides supportive evidence of an association between arsenic exposure in drinking water and skin manifestations, and highlights the need for future longitudinal studies using individual-level exposure measures and more comprehensive control of confounding factors.

Author contributions

ARR: Methodology, validation, formal analysis, writing—original draft, and review. SKH & FS: Conceptualization, methodology, validation, data curation, formal analysis, investigation, resources, and writing—original draft. SHN, MKh & SS: Clinical assessment; sampling and data collection. AD-I: Methodology, statistical analysis, review & editing. SBA & LR: Water sampling and arsenic detection. OS: Revision of the manuscript, critical review, and preparation of detailed responses to reviewers’ comments.

Funding

This work was supported by the Vice Chancellery for Research at Hamadan University of Medical Sciences [Grant No. 140106155054].

Data availability

All data generated or analyzed in this study are included in this published article.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The protocol and ethics of this study were approved by the Ethics Committee of Hamadan University of Medical Science (Ethic Code of IR. UMSHA.REC.1401453), and all the participants provided their informed written consent, agreed to provide samples, and received no payment for their participation.