We investigated the association between total and specific-crop densities in the municipalities of residence at birth and childhood leukaemia incidence rates in the population of children born in 1990-2015. In all, we did not observe any statistically significant positive association between total childhood AL, ALL and AML incidence rates and any crop type. Interestingly, the incidence rate of AL was slightly higher in children living at birth in the municipalities with the highest viticulture densities (SIR=1.25 95%CI [1.01-1.54] in the highest semi-quartile of exposure), which was in line with our study on residences at diagnosis (Coste et al., 2020).
Based on the same methodology and same agricultural data, we evidenced a log-linear increase in ALL incidence rate over the period 1990-2014 with increasing viticulture density in the municipality of residence at diagnosis (SIRR=1.04 95%CI [1.00-1.06] per 10% increase) and an increase in ALL incidence rate in the municipalities with the highest viticulture density (i.e. with more than a quarter of their area used for viticulture, SIR=1.17 95%CI [1.01-1.35]) (Coste et al., 2020). Although the result of the present study is not statistically significant, and less marked than in our previous study, it provides some support for the hypothesis that there is a positive association between childhood AL incidence and viticulture density in the municipalities. However, the weakness of the association does not suggest that our previous results can be explained by prenatal exposures.
Viticulture is all the more of interest in that vines are a permanent crop subject to many pesticide treatments, particularly fungicidal treatments. Few studies have investigated the role of residential exposure to agricultural pesticides in the occurrence of childhood AL using proximity to croplands as a surrogate (Additional. Table 6). Most of the studies were conducted in the USA. With a large number of cases (6,168 AL), Carozza et al. (Carozza et al., 2008) considered the percentage cropland devoted to farming at the county level and showed a positive association between total cropland (≥60% of county total acreage vs < 20%) and ALL and AML risk (OR=1.3 95%CI [1.1-1.4], and OR=1.8 95% CI [1.4-2.3], respectively). The authors also reported positive associations with some specific crops (maize and soya bean densities for AML, oats density for ALL). In a study by Booth et al. (Booth et al., 2015) conducted in 6 Midwestern states, 0-4-year AL and ALL, incidence rates were associated with dry beans and sugar beet in exposure-response analyses. A positive association between 0-4-year AML incidence rates and oats density was also reported. More recently, a study conducted in California reported a greater ALL risk in children residing close to plant nurseries at birth (OR for <75 m vs ≥ 600 m of 3.09 95% CI [1.14-8.34] (Nguyen et al., 2021)). Conversely, three Texan studies (Carozza et al., 2009; Thompson et al., 2008; Walker et al., 2007) did not evidence any association between childhood AL and agricultural area in the county of residence at birth (Thompson et al., 2008; Walker et al., 2007) or within a 1000-m buffer around the geocoded address of residence at birth (Carozza et al., 2009). In addition to our previous ecological study (Coste et al., 2020), three studies have been conducted in Europe (Gómez-Barroso et al., 2016; Malagoli et al., 2016; Patel et al., 2020). In Italy, in a case-control study with 111 AL cases and 444 matched controls, Malagoli et al. did not find any association between AL risk and arable crop, orchard, vineyard or vegetable densities (Malagoli et al., 2016), while, in Spain, Gomez-Barroso et al. reported an elevated risk of leukaemia (1,062 cases) with total crop density and several specific crop densities (arable land or permanently irrigated land; rice fields; heterogeneous agricultural areas) (Gómez-Barroso et al., 2016). The study also found strong associations with other childhood cancer types; it is unclear whether those results may be due to different addresses being used for the cases (at diagnosis) and controls (at birth). A recent Danish cohort study (Patel et al., 2020) found a 2-fold increase in leukaemia risk (61 AL cases) for children whose mothers lived close to agricultural areas during pregnancy (≥ 24 ha of total agricultural land within a 500-m buffer), in particular when grass/clover, peas and maize crops were present.
Several studies thus reported positive associations between childhood AL risk and proximity to cropland, particularly around diagnosis (Booth et al., 2015; Carozza et al., 2008; Coste et al., 2020; Gómez-Barroso et al., 2016; Malagoli et al., 2016; Patel et al., 2020). However, the estimates of the reported associations were sometimes imprecise due to the limited numbers of cases (Gómez-Barroso et al., 2016; Malagoli et al., 2016; Patel et al., 2020). In addition, the positive associations reported in several studies were for total crop density (Carozza et al., 2008; Gómez-Barroso et al., 2016; Patel et al., 2020), which may not be a relevant surrogate for pesticide exposure because of the heterogeneity of the crops included, especially in terms of pesticide use. It is difficult to compare our results with those from other countries because of differences in agricultural areas and practices (FAO, 2019). For example, in the USA, positive associations were reported with dry beans, sugar beet (Booth et al., 2015), oats (Booth et al., 2015; Carozza et al., 2008), maize and soya beans (Carozza et al., 2008), which are less common crops in France (FAO, 2019).
We used agricultural census data to estimate crop densities in the municipalities of residence at birth, as indicators of potential exposure to agricultural pesticides. A limitation consists in the fact that the census locates the crops in the municipality of the farm headquarters, while the crops may be located in neighbouring municipalities. However, the resulting misclassifications most likely affect similar agricultural areas close to each other and preserve contrasts between exposed and unexposed municipalities. Another limitation is that we assigned the agricultural census closest to the year of birth, which may have induced misclassification for rotational crops when the years of census and birth differed. This limitation should not affect the classification of permanent crops like vineyards and arboriculture. Moreover, the results remained unchanged in the sensitivity analyses restricted to children born in 1990-2004, before many vines were uprooted.
The agricultural censuses do not distinguish organically-farmed fields from conventionally-farmed fields. However, organically-farmed fields constitute only a small fraction of the agricultural area of France; they accounted for 9.5% of the total agricultural area in 2019 (Ministère de agriculture et de l’alimentation, 2021) and probably less during our study period since organic farming was less widespread. Moreover, two surveys of agricultural practices showed that more than 90% of the areas covered by the crops we considered in our study had received at least one pesticide treatment in 2006 and 2011 (Ministère de l’agriculture et de l’alimentation, 2014, 2010).
Adjustments for the degree of urbanization, deprivation and UV radiation, which were associated with childhood ALL incidence rate at the municipality level in our previous studies, did not change the result. We were unable to take individual factors like domestic pesticide use and parental agricultural occupation into account. Even if those factors are more prevalent in the most agricultural municipalities, the proportion of children with a parent occupationally exposed to pesticides is very low in France (Bailey et al., 2014). Maternal use of pesticides during pregnancy is much more common, about 35% for control mothers in two French case-control studies (Mavoungou et al., 2020; Rios et al., 2017; Rudant et al., 2007; Vidart d’Egurbide Bagazgoïtia et al., 2018) but not restricted to agricultural areas. Residential exposure to traffic-related air pollution, which was associated with the risk of childhood AML (Amigou et al., 2011; Houot et al., 2015), could not be accounted for. However, the results were unchanged after exclusion of the municipalities in urban units with a population greater than 100,000, where those associations were observed.
Our study has several strengths. A major asset is that our findings are based on a large number of cases, identified from a population-based registry. The high degree of completeness, avoided selection biases, and the high standard of diagnosis classifications and high reliability of addresses (3% missing addresses) minimised misclassifications. Another asset is the use of agricultural census data, collected on an exhaustive basis and providing the detailed distribution of ten types of crops on the fine scale of the municipality for the entire country. The crop types are known to be quite different in terms of average annual number of pesticide treatments, percentage of area treated, and main target pesticide, with variations between time periods and regions (Ministère de l’agriculture et de l’alimentation, 2014, 2010). A few Californian studies benefitted from the Pesticides Use Reporting (PUR) system, with a large database on pesticides applied to crops in the state of California, to investigate for associations with childhood leukaemia (Park et al., 2020; Reynolds et al., 2005b, 2005a, 2002; Rull et al., 2009). Some positive associations with specific substances or classes of pesticide have been reported, with, however, heterogeneous results: AL risk was thus associated with high use of propargite near the residence at diagnosis in Reynold et al. 2002 (Reynolds et al., 2002); a moderate lifetime averaged use of insecticides and fumigants in the vicinity of the addresses of residence in Rull et al. (Rull et al., 2009); the use of metam sodium and dicofol near the residence at birth for children aged 0-4 years in Reynold et al. 2005 (Reynolds et al., 2005b); and the uses of any carcinogenic pesticide, several chemical classes or individual pesticides near the residence at birth for children aged less than 6 years in Park et al. (Park et al., 2020).
Our next step will be to conduct a large case-control study using geocoded addresses and a geographical information system in order to evaluate, as precisely as possible, the presence of cropland in the vicinity of the residential addresses, with a particular focus on viticulture. Elucidating the relationship between the ecological and individual crop proximity indicators will be of great importance. Future challenges will then consist in enhanced assessment of the role of agricultural pesticide exposure and identification of the specific substances potentially involved in childhood leukaemia.