Childhood leukaemia and exposure to pesticides: Results of a case-control study in Northern Germany

doi:10.1016/0959-8049(96)00231-6

European Journal of Cancer

Volume 32, Issue 11, October 1996, Pages 1943-1948

https://doi.org/10.1016/0959-8049(96)00231-6 Get rights and content

Abstract

The association between childhood leukaemia and exposure to pesticides was examined in a population-based case-control study conducted in Lower Saxony, Northern Germany. Between July 1988 and June 1992, 219 newly diagnosed cases were identified, of whom 173 participated in the study. Two sex- and age-matched control groups were recruited: local controls from the same communities as the newly diagnosed cases of leukaemia and state controls from other randomly selected communities in Lower Saxony. An additional study group consisted of 175 cases of solid tumours. When the leukaemia cases were compared with the local controls, positive associations with parental occupational exposure, particularly agriculture-related exposure, were observed, which were statistically non-significant. A significant association was found for pesticide use in gardens (odds ratio = 2.52, 95% confidence interval: 1.0–6.1). No positive associations were seen when the leukaemia cases were compared to the state controls, but this finding could be explained by a higher proportion of state controls living in rural areas. In communities with a significantly elevated standardised incidence ratio of childhood leukaemia over the last decade (1984–1993), the prevalence of pesticide use in the garden was 21%, compared with the 10% in other communities. None of the examined risk factors were more common among cases of solid tumours. Our findings add some evidence to the hypothesis that pesticides are a risk factor for childhood leukaemia, and there are good reasons to consider abundant pesticide use in rural areas as a possible cause for clustering of childhood leukaemia.

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Cited by (62)

Exposure to pesticides and childhood leukemia risk: A systematic review and meta-analysis
2021, Environmental Pollution
Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15–3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39–4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00–1.99) and insecticide (OR: 1.60, 95%CI: 1.11–2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12–0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44–3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98–5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (OR_parental: 1.75, 95%CI: 1.08–2.85; OR_paternal: 1.20, 95%CI: 1.07–1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.
Household exposure to pesticides and risk of leukemia in children and adolescents: Updated systematic review and meta-analysis
2019, International Journal of Hygiene and Environmental Health
Citation Excerpt :
One of them (Bailey et al., 2015) is a pooled analysis including data from 12 case-control studies. In the third step (identifying redundancies among full text articles to be assessed for eligibility), checking for redundancy of studies issued from step (i) resulted in the exclusion of 7 case-control studies (Infante-Rivard et al., 1999; Ma et al., 2002; Meinert et al., 1996, 2000; Menegaux et al., 2006; Rudant et al., 2007; Urayama et al., 2007) as they were included in the pooled analysis of Bailey et al. (2015). Two additional studies were excluded: the study of Pombo-de-Oliveira and Koifman (2006) as it was updated by Ferreira et al. (2013) and the study of Spix et al. (2009) as it was a duplicate, also identified in step (ii).
The role that pesticides in the domestic environment might play in the etiology of childhood leukemia remains a subject of controversy. Recent studies often reached inconsistent conclusions.
To update our earlier systematic review on the association between residential/household/domestic exposure to pesticides and childhood leukemia, and to explore potential sources of heterogeneity not previously assessed.
A systematic search of studies published in English between January 2009 and June 2018 was conducted in MEDLINE, and a “snowball searching” was performed from the reference list of identified publications and from Web of Science citations. Risk estimates were extracted from 15 case-control studies published between 1987 and 2018. The quality of the publications was assessed by using a modified version of the Downs and Black (1998) checklist. A random-effect meta-analysis model was used to calculate summary odds ratios (SOR) and separate analyses were conducted for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), unspecified AL/leukemia and any leukemia types. Stratification by critical exposure period, exposure location, pesticide biocide category, child age at diagnosis, study quality, specific exposures, type of pest treated, and geographic location were performed.
A statistically significant association between residential pesticide exposure and childhood leukemia was observed by combining all studies (SOR: 1.57; 95% CI: 1.27–1.95) without evidence of publication bias. Statistically significant increased risks were observed for all types of leukemia, and specifically for exposure during pregnancy, indoor exposure, prenatal exposure to insecticides and whatever the age at diagnosis. Statistical significance was also reached for high quality studies, pet treatments, professional pest control treatment and use of insect repellants, mosquito treatment and for studies from USA/Canada or International. The highest increased risks were observed for AML among children aged 2 years or less, as well as for unspecified leukemia type observed after prenatal indoor exposure.
A positive association between domestic pesticide exposure and childhood leukemia is confirmed. Although the literature provides moderate to low-quality of evidence, these new results further justify the need of limiting the use of household pesticides during pregnancy and childhood.
Livestock and poultry density and childhood cancer incidence in nine states in the USA
2017, Environmental Research
Citation Excerpt :
Many of these studies did not evaluate relationships separately for specific animal types, which is important because exposures to chemical and biological agents may vary by animal species and animal management practices (Spellman and Whiting, 2007). Most studies of childhood leukemia found no associations with parental or childhood exposure to animals (Keegan et al., 2012; Kristensen et al., 1996; McKinney et al., 2003; Meinert et al., 1996; Rudant et al., 2010; van Steensel-Moll et al., 1985); whereas most studies of CBTs found positive associations with parental or childhood exposure to animals (Christensen et al., 2012; Efird et al., 2003; Holly et al., 1998; Keegan et al., 2013; Kristensen et al., 1996). Ecologic studies in the United States have evaluated relationships between county-level incidence rates of childhood cancers and the density of specific crop types as a proxy for potential agricultural pesticide exposure (Booth et al., 2015; Carozza et al., 2008).
Parental occupational and childhood exposures to farm animals have been positively associated with childhood brain tumors, whereas associations with childhood leukemia are equivocal. The developing immune system may be influenced by allergen, virus, or other exposures from animal sources, which may contribute to childhood cancer incidence.
Incident cancers (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], central nervous system [CNS], peripheral nervous system [PNS]) for children aged 0–4 diagnosed between 2003 and 2008 were obtained from nine National Cancer Institute Surveillance, Epidemiology and End Results (SEER) registries and were linked to U.S. Census of Agriculture data from 2002 and 2007 by county of diagnosis. Animal densities (animal units [AU]/km²; one animal unit is 1000 pounds of animal weight) were estimated for hogs, cattle, chickens (layers and broilers, separately), equine (horses, ponies, mules, burros, donkeys), goats, sheep, turkeys, and total animals. Animal density was examined in models as both continuous (AU per km²) and categorical variables (quartiles). Animal operation densities (per km²) by size of operation (cattle, hogs, chickens, sheep) were modeled continuously. Rate ratios and 95% confidence intervals were estimated using Poisson regression.
We found positive associations between AML and broiler chicken densities (RR_{per 10 AU/km}² = 1.14, 95% CI = 1.02–1.26). ALL rates increased with densities of hog operations (RRper operation/100 km² = 1.06, 95% CI = 1.02–1.11). PNS cancer rates were inversely associated with layer chicken density (RR_{per log of AU/km}² = 0.94, 95% CI = 0.89–0.99). No association was found between any cancer type and densities of cattle, equine, or goats.
Although limited by the ecologic study design, some of our findings are novel and should be examined in epidemiological studies with individual level data.
Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives
2013, Toxicology and Applied Pharmacology
Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action.
Reliability of maternal-reports regarding the use of household pesticides: Experience from a case-control study of childhood leukemia
2012, Cancer Epidemiology
Citation Excerpt :
Similarly, eight other studies reported positive and significant results for the association between childhood leukemia and household pesticide use during pregnancy [6–12] and five studies reported significant results for exposure in early childhood [7–11]. In addition, five studies showed significant associations with garden products used during pregnancy [8,10,12] and early childhood [8,10,11,13]. These studies, and six more, were included in a recent meta-analysis, by Turner et al. [14].
Introduction: Self-reported household pesticide use has been associated with higher risk of childhood leukemia in a number of case–control studies. The aim of this study is to assess the reliability of self-reported household use of pesticides and potential differences in reliability by case–control status, and by socio-demographic characteristics. Methods: Analyses are based on a subset of the Northern California Childhood Leukemia Study population. Eligible households included those with children less than 8 years old who lived in the same residence since diagnosis (reference date for controls). The reliability was based on two repeated in-person interviews. Kappa, percent positive and negative agreements were used to assess reliability of responses to ever/never use of six pesticides categories. Results: Kappa statistics ranged from 0.31 to 0.61 (fair to substantial agreement), with 9 out of the 12 tests indicating moderate agreement. The percent positive agreement ranged from 46 to 80% and the percent negative agreement from 54 to 95%. Reliability for all pesticide types as assessed by the three reliability measures did not differ significantly for cases and controls as confirmed by bootstrap analysis. For most pesticide types, Kappa and percent positive agreement were higher for non-Hispanics than Hispanics and for households with higher income vs. lower income. Conclusions: Reproducibility of maternal-reported pesticide use was moderate to high and was similar among cases and controls suggesting that differential recall is not likely to be a major source of bias.
Residential exposure to pesticides and childhood leukaemia: A systematic review and meta-analysis
2011, Environment International
Citation Excerpt :
Three studies of the “after pregnancy” window reported data on exposure from birth to diagnosis (Infante-Rivard et al., 1999; Meinert et al., 2000; Menegaux et al., 2006), two on exposure during year 1 after birth (Buckley et al., 1989; Ma et al., 2002) and Leiss and Savitz (1995) considered exposure from birth to 2 years prior to diagnosis and from 2 years prior to diagnosis through diagnosis. The last window of exposure includes less clearly defined exposure windows (Lowengart et al., 1987: exposure during pregnancy or nursing; Spix et al., 2009: since conception) or longer durations of exposure: from 1 month before pregnancy to the end of pregnancy (Infante-Rivard et al., 1999), from 3 months before pregnancy to 3 years old (Ma et al., 2002), from 2 years before birth up to diagnosis (Meinert et al., 1996) and at any time from 1 year before birth through the first 3 years of life (Urayama et al., 2007). Table 2 summarises the results of the different meta-analyses as well as the assessment of inconsistency (heterogeneity).
To conduct a systematic review of published studies on the association between residential/household/domestic exposure to pesticides and childhood leukaemia, and to provide a quantitative estimate of the risk.
Publications in English were searched in MEDLINE (1966–31 December 2009) and from the reference list of identified publications. Extraction of relative risk (RR) estimates was performed independently by 2 authors using predefined inclusion criteria. Meta-rate ratio estimates (mRR) were calculated according to fixed and random-effect models. Separate analyses were conducted after stratification for exposure time windows, residential exposure location, biocide category and type of leukaemia.
RR estimates were extracted from 13 case-control studies published between 1987 and 2009. Statistically significant associations with childhood leukaemia were observed when combining all studies (mRR: 1.74, 95% CI: 1.37–2.21). Exposure during and after pregnancy was positively associated with childhood leukaemia, with the strongest risk for exposure during pregnancy (mRR: 2.19, 95% CI: 1.92–2.50). Other stratifications showed the greatest risk estimates for indoor exposure (mRR: 1.74, 95% CI: 1.45–2.09), for exposure to insecticides (mRR: 1.73, 95% CI: 1.33–2.26) as well as for acute non-lymphocytic leukaemia (ANLL) (mRR: 2.30, 95% CI: 1.53–3.45). Outdoor exposure and exposure of children to herbicides (after pregnancy) were not significantly associated with childhood leukaemia (mRR: 1.21, 95% CI: 0.97–1.52; mRR: 1.16, 95% CI: 0.76–1.76, respectively).
Our findings support the assumption that residential pesticide exposure may be a contributing risk factor for childhood leukaemia but available data were too scarce for causality ascertainment. It may be opportune to consider preventive actions, including educational measures, to decrease the use of pesticides for residential purposes and particularly the use of indoor insecticides during pregnancy.

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Original paperChildhood leukaemia and exposure to pesticides: Results of a case-control study in Northern Germany

Abstract

Hum Pathol

Eur J Cancer

Childhood leukemia and parents' occupational and home exposures

J Natl Cancer Inst

A population-based case-control study of childhood leukemia in Shanghai

Cancer

Occupational exposure of parents of children with acute nonlymphocytic leukemia. A report from the Childrens Cancer Study Group

Cancer Res

Risk factors associated to development of leukemia in children

Bol Med Hospital Infantil Mexico

Case-control study on the association between a cluster of childhood hematopoietic malignancies and local environmental factors in Aalsmeer

J Epidemiol Community Health

Epidemiological characteristics of childhood acute lymphocytic leukemia. Analysis by immunotype

Leukemia

Home pesticide use and childhood cancer: a case-control study

Am J Public Health

Risk factors for brain tumors in children

Am J Epidemiol

N-nitroso compounds and childhood brain tumors: a case-control study

Cancer Res

An exploratory case-control study of brain tumors in children

Cancer Res

Original paper
Childhood leukaemia and exposure to pesticides: Results of a case-control study in Northern Germany