Numerous epidemiologic studies have investigated the potential association between childhood leukemia and paternal ionizing radiation exposure in the workplace before conception or preconception, also referred to as “preconception paternal irradiation” (PPI). Some studies have found an association (Gardner 1991; Gardner et al. 1990; McKinney et al. 1991; Meinert et al. 1999; Roman et al. 1993; Shu et al. 1994), whereas others have not (Doll et al. 1994; Kinlen et al. 1993; Little 1990; McLaughlin et al. 1993; Shu et al. 2002; Urquhart et al. 1991; Watson 1991).

Gardner et al. (1990) examined whether the observed excess of childhood leukemia was related to nearness to Sellafield nuclear plant in the West Cumbria district of the United Kingdom from 1950 to 1985. Relative risk was higher for leukemia in children born near Sellafield and for children of fathers employed at the plant at their conception [relative risk (RR) = 2.4; 95% confidence interval (CI), 1.04–5.7] and higher for children of fathers receiving a total preconceptual ionizing radiation dose of 100 mSv or more (RR = 6.4; 95% CI, 1.57–26.3). Gardner et al. (1990) hypothesized that irradiation of the testes may be leukomogenic in the offspring. The conclusions of this study have received significant criticism (Doll et al. 1994; Neel and Schull 1991). First, no excess leukemia was noted in the rest of Cumbria where > 90% of the births to Sellafield employees occurred (Draper et al. 1993). Second, data on the children of male atomic bomb survivors have not shown an increased incidence of leukemia (Yoshimoto et al. 1990), despite receiving a significantly greater dose of radiation than the children’s fathers at Sellafield. The results reported by Gardner et al. (1990) would suggest a much greater genetic sensitivity to radiation and therefore would be less plausible (Doll et al. 1994; Little 1990). Third, the results from the Gardner et al. (1990) study have not been substantiated by other studies that detected no statistically significant excess of leukemia in relation to nuclear facilities in the following locations:

McKinney et al. (1991) did show a nonstatistically significant increase between childhood leukemia and reported preconceptual exposure of fathers to ionizing radiation [odds ratio (OR) = 2.35; 95% CI, 0.92–6.2]. This study overlapped with another study and the quantity of the exposure to ionizing radiation was not determined (McKinney et al. 1991).

With regard to diagnostic X rays, Shu et al. 1994) showed an increased risk for childhood leukemia related to paternal diagnostic x-ray exposure before conception in two separate studies. In the 1994 study, an increased risk was noted if two or more X rays of the lower abdomen were performed (OR = 3.8; 95% CI, 1.5–9.6). No increased risk was noted in the Shu et al. (2002) study, however, if the data were restricted to lower abdominal X rays, the more relevant area of exposure.

Mechanisms of potentiation by PPI are discussed in detail elsewhere (Lord 1999). Maternal preconception occupational exposure has not been shown to significantly increase the risk for childhood leukemia (Meinert et al. 1999; Shu et al. 1994).

Many studies have attempted to ascertain the effect of in utero radiation exposure and the development of leukemia—particularly related to the atomic bomb exposures in Japan at the end of World War II, the 1986 Chernobyl (Russia) accident, or exposure to diagnostic X rays. An increased risk of childhood leukemia in the offspring of atomic bomb survivors has yet to be shown (Doll and Wakeford 1997; Neel 1991; Yoshimoto et al. 1988). Some studies on the Chernobyl accident, which led to widespread radioactive fallout in Europe, have found an increased risk for leukemia in children exposed in utero while living in areas exposed to ionizing radiation after the accident (Noshchenko et al. 2001; Petridou et al. 1996). The observed effects are in question, however, and other studies have not confirmed an increase in risk (Michaelis et al. 1997; Sali et al. 1996; Steiner et al. 1998).

In a critical review of several European studies undertaken 10 years after Chernobyl, overall, no significant association between the risk of childhood leukemia in children 0–14 years of age and exposure from the Chernobyl accident was found (Sali et al. 1996). However, a small risk could not be ruled out secondary to limited power and the fact that most studies were descriptive. In a Swedish study, the risk for ALL in children < 5 years of age in highly contaminated areas was increased although not statistically significant (OR = 1.5; 95% CI, 0.8–2.6) (Hjalmars et al. 1994). Last, in a review of 36 cancer registries in Europe for children 0–14 years of age, the risk for leukemia was increased slightly in the postaccident period, but the overall geographical patterns of change uncovered no relation to the estimated exposure to radiation (Parkin et al. 1993, 1996).

Many studies have assessed the risk of in utero exposure to diagnostic X rays and the development of childhood leukemia, with conflicting results. The potential risk of leukemia in children exposed to diagnostic X rays was first noted in 1956 (Stewart et al. 1956). Many case–control studies have found a consistent association to suggest that radiographic examination of the abdomen of a pregnant woman produces a proportional increase in risk of about 40% (Doll and Wakeford 1997). The evidence for causality and for uncertainty is well described (Boice and Miller 1999; Doll and Wakeford 1997). The most notable reason for doubt of a true association is the lack of evidence in cohort studies for an increased risk of leukemia in children exposed to radiation in utero during the atomic bomb blasts in Japan. Furthermore, several recent studies have not found a significant association between childhood leukemia and X-ray examinations in the mother during pregnancy (Meinert et al. 1999; Naumberg et al. 2001; Shu et al. 2002). This apparent decrease in risk over time may be attributable to declining exposures to ionizing radiation (decreased dose) and to the increasing use of diagnostic ultrasound in place of diagnostic X rays during pregnancy (Shu et al. 2002).

Postnatal exposure to ionizing radiation has been demonstrated to increase the risk of childhood leukemia, most notably from the World War II atomic bomb blasts and radiotherapy for benign disease. Children and adolescents exposed to 1 gray after the bombings were at elevated risk for leukemia (RR = 7.1) and developed leukemia in less time when compared with adults (Boice 1996). Several studies have identified an increased risk for childhood leukemia or death due to leukemia secondary to radiotherapy of benign disease (Darby et al. 1987; Davies et al. 1961; Murray et al. 1959; Ron et al. 1988) whereas others have not (Lundell and Holm 1996) (Table 1). This risk appears to be associated with therapeutic radiation for thymus enlargement, ankylosing spondylitis, and ringworm.

Although inconclusive, to date, radiation exposure secondary to the Chernobyl accident has not been shown to increase the risk of leukemia in children who were exposed after birth (Moysich et al. 2002; Parkin et al. 1993, 1996; Sali et al. 1996). Recent studies have shown mixed results regarding exposure to diagnostic X rays during the postnatal period and the risk for childhood leukemia (Meinert et al. 1999; Shu et al. 2002) (Table 1). Shu et al. (2002) found no significant risk for ALL, even if there were exposure to three or more rays (OR = 1.2; 95% CI, 1.0–1.6). They did note a significant risk for children with pre-B cell ALL, most notably if three or more X rays were performed (OR = 3.2; 95% CI, 1.5–7.2) and if the child was older than 5 years (OR = 3.8; 95% CI, 1.1–13.3). Meinert et al. (1999) found that exposure to four or more X rays in the postnatal period did not contribute a significant risk to childhood leukemia (OR = 2.3; 95% CI, 0.8–6.5); however, the risk was not evaluated by immunophenotype. Overall, postnatal X-ray studies do not appear to significantly increase the risk of childhood leukemia. Increased risk for specific immunophenotypes may result from certain biases, but this may be an area for further study.

Hydrocarbons are organic compounds made up primarily of carbon and hydrogen atoms. Examples of hydrocarbon compounds include gasoline and trichloroethylene (spot remover). Hydrocarbons are found in many household and industrial products including paint removers and thinners, and solvents, which are used to dissolve other chemical substances.

The most widely recognized hydrocarbon is benzene, a ubiquitous chemical used in the manufacture of paints and plastics and as a constituent in motor fuels and hobby glues. It is also formed during incomplete combustion of fossil fuels (i.e., petroleum products, coal). Benzene is a known human carcinogen. It has a strong positive exposure–response relationship with leukemia, particularly AML, at a range of exposures not much higher than the current legal standard for workers as recommended by the National Institute for Occupational Safety and Health (Rinsky 1981). A recent occupational study (Glass 2003) found excess risk for leukemia associated with cumulative benzene exposures and benzene exposure intensities at lower levels (< 60 ppm-years) than had been previously reported (as high as 220 ppm-years) (Rushton and Romaniuk 1997; Schnatter et al. 1996). For additional information on benzene, see Supplemental Material (http://www.ehponline.org/docs/2006/9023/abstract.html).

Freedman et al. (2001) conducted a case-control study of 640 subjects to examine the relationship between parental hobbies and home projects and incidence of childhood leukemia. ALL had a statistically significant association with prenatal exposure to painted homes (> 4 rooms) (OR = 1.7; 95% CI, 1.1–2.7) and to artwork with solvents (OR = 4.1; 95% CI, 1.1–15.1). However, the study was limited by the lack of information about the child’s proximity to the activity and the timeframe of exposure.

In a review by Savitz and Chen (1990) of seven published epidemiologic studies of the association between parental occupation and childhood leukemia, exposure to paints and pigments yielded the most consistently positive results, with several studies producing ORs for ALL and AML of ≥ 1.5. Paternal occupations most associated with increased risk for childhood leukemia in the review included painter, motor vehicle–related worker and machinist or factory worker. In one of the seven epidemiologic studies reviewed, paternal hydrocarbon exposures (e.g., gas station attendant) appeared to be related to both AML and ALL occurring in children ≤ 1 year of age (Vianna et al. 1984), but this finding could not be confirmed by other studies that covered a broader age range (Van Steensel-Moll et al. 1985).

In a separate large case–control study, only paternal long-term exposure to plastics during the preconception period showed an increased risk of childhood leukemia, though not statistically significant (OR = 1.4; 95% CI, 1.0–1.9) (Shu et al. 1999b).

There is much speculation about the biological mechanism by which paternal occupational exposures may affect the offspring’s risk for leukemia. Potential mechanisms include genetic alteration of the father’s sperm, which may transmit cancer susceptibility to the child, transplacental fetal exposure after the father brings a toxic exposure into the home, and direct postnatal exposure to chemicals brought home on the clothing (e.g., off-gassing) (Buckley et al. 1989; Savitz and Chen 1990) or indirect exposure through breast-feeding. Exposure through breast milk, however, is an unlikely mechanism as breast-feeding has been associated with a reduced risk of ALL (Shu et al. 1999a). The reduction in risk was stronger with a longer duration of breast-feeding.

Specific occupations found more frequently among mothers of children with leukemia include metal manufacturing or processing, textiles, and pharmacist (Savitz and Chen 1990; Van Steensel-Moll et al. 1985). Increased risk for ALL has been described, in a case–control study of more than 3500 children, with maternal occupational exposure to solvents (OR = 1.8; 95% CI, 1.3–2.5) and paints (OR = 1.6; 95% CI, 1.2–2.2) during the preconception period (OR = 1.6; 95% CI, 1.3–2.5), and during pregnancy (OR = 1.7; 95% CI, 1.2–2.3), but not during the postnatal period (Shu et al. 1999b). Despite these associations, no linear dose–response relationship was observed in this study for any maternal exposure during any time period, and statistically significant associations were found only when maternal occupational exposures were short (equal or below the median) (Shu et al. 1999b).

A recent study in California suggested that children living in areas with high levels of point source carcinogenic hazardous air pollutants (HAPs) are at an increased risk of developing leukemia (RR = 1.3; 95% CI, 1.13–1.6) (Reynolds et al. 2003). Selected carcinogenic HAPs included benzene, perchloroethylene, and trichloroethylene. This study had several limitations; most notably the extrapolation of group exposure levels to individuals and exclusion of indoor HAP sources (e.g., tobacco smoke) as potential confounders of exposure estimates (Reynolds et al. 2003).

A recent, similar study in Great Britain reported associations between birthplace of children with leukemia and proximity to industrial sites that release volatile organic compounds, dioxins, 1,3-butadiene, and benzo[a]pyrene (Knox 2005).

Many studies have suggested a link between pesticide exposure and childhood leukemia. However, most of these studies are limited by the use of nonspecific pesticide exposure information, small numbers of exposed children, and potential recall bias. Some studies suggest that pesticide-exposed fetuses and children are at higher risks for cancer compared with adults. This suggests that newborns and children may be particularly sensitive to the carcinogenic effects of pesticides (National Research Council 1993; Zahm and Ward 1998). Most children’s exposure to pesticides is from home, lawn, and garden use (Grossman 1995). Other sources of exposure can include local agricultural applications, contaminated food, parental occupation, and pet products.

In a large meta-analysis of epidemiologic studies that investigated whether occupational or residential exposure to pesticides by either parents or children was related to increased risk of childhood cancer, frequent occupational exposure or in-home pesticide use was associated with childhood leukemia (Daniels et al. 1997) (Table 2). Use of garden pesticides or professional exterminations did not greatly affect risk in this meta-analysis. Some studies have reported increased risk with mothers who had frequent prenatal pesticide exposure in the garden (Infante-Rivard et al. 1999) or during pregnancy (OR = 6.5; 95% CI, 1.5–59) (Lowengart 1987) and increased risk during childhood with garden insecticides (OR = 2.4; 95% CI, 1.3–4.3) and garden fungicides (OR = 2.5; 95% CI, 1.0–6.2) (Menegaux et al. 2006).

Children exposed to professional pest control services at any time 1 year before birth to 3 years after had increased risk as well (OR = 2.8; 95% CI, 1.4–5.7) (Ma 2002) (Table 2). In a review of 18 studies that assessed the association between pesticide exposure and childhood cancer, no clear patterns of risk by which parent was exposed, by timing of exposure, or by histologic type of leukemia were apparent (Zahm and Ward 1998).

In a recent case–control study conducted in France, for the first time insecticidal shampoo treatment of pediculosis was found to be associated with childhood ALL and AML (OR = 1.9; 95% CI, 1.2–3.3) (Menegaux et al. 2006). Various insecticidal shampoos were reported but only the association with pyrethroid-based shampoo was statistically significant (OR = 2.0; 95% CI, 1.1–3.4) (Menegaux et al. 2006).