International Patterns

A wide variation exists in the incidence of childhood leukemia by geographic location. The highest annual incidence rates are reported in Costa Rica, Ecuador, Hong Kong, Denmark, and Singapore (57.9 to 51.0 per million population), whereas some of the lowest rates are found in Zimbabwe, India, Israel, and Algeria (23.1 to 26.0 per million). The annual incidence of childhood leukemia for many regions, including North America, Australia, Northern and Western Europe, China, Japan, the Philippines, and Singapore, ranges between 35 and 50 per million ( Table 40-1 ). When evaluating geographic variation in disease incidence, concerns always exist regarding the quality and completeness of reporting. Ecologic studies of childhood leukemia incidence according to annual per-capita gross national income demonstrates substantial variation within low-income countries and a much narrower range in middle- and high-income countries. In addition, a significant correlation exists between the incidence of childhood leukemia and population mortality rates for children younger than 5 years in low- and middle-income countries. Some of the lowest reported childhood leukemia rates are within countries with high mortality rates for children younger than 5 years, suggesting that children with undiagnosed leukemia may die in some low-income countries as a result of anemia or fever that is attributed to infectious disease.

Age-Specific Incidence and Sex Ratio

The incidence rate for all leukemias is highest among children younger than 5 years and decreases with age. The age-adjusted incidence for boys exceeds that for girls, with a sex ratio typically between 1.1 : 1 and 1.4 : 1.

Acute Lymphoblastic Leukemia

In developed countries, the age-incidence curve for ALL is characterized by a peak between the ages of 1 and 4 years ( Fig. 40-1 ). Thus a sharp peak in ALL incidence is seen among 2- to 3-year-olds (>100 per million), which decreases to a rate of 20 per million for 8- to 10-year-olds. The incidence of ALL among 2- to 3-year-olds is approximately fourfold greater than that for infants and is nearly tenfold greater than that for 19-year-olds. Although this age distribution is well recognized and attributable to common ALL (cALL), it has not always been present. It was first observed in England and Wales in the 1920s, among American whites in the 1940s, among African Americans and in Japan in the 1960s, and among Jews and non-Jews in Israel in the 1970s. In Kuwait, where the incidence was low during the 1970s, the age peak has recently been observed, whereas in the African series, in which the incidence is also low, the peak has not yet been reported.

Incidence of leukemia (per million children) by age at diagnosis. ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome.

An exaggerated peak incidence among 2- to 3-year-olds, with a very low incidence of ALL in older children, was observed in certain areas of England and Wales and in the rural north of Scotland and coincided with a high socioeconomic status. These observations have led to a hypothesis that an elevated risk of ALL is influenced by community characteristics such as isolation, high socioeconomic status, and population mixing, which in turn are related to immunologic isolation in infancy and influence patterns of exposure to common infectious agents in the early years of life before the appearance of leukemia. These hypotheses are discussed in detail later. The ratio of incidence rates of ALL for boys and girls ranges between 1.1 : 1 and 1.3 : 1.

Ethnic Origin

In the United States, substantial variation is seen in the incidence rates of ALL by ethnicity. The highest rates are reported among Hispanics, Filipinos, and Chinese, and the lowest rates are reported among African Americans. The incidence rates among whites are moderate to high by international standards, whereas those for American Indians are somewhat lower.

On the other hand, two studies have investigated the incidence of childhood cancer by ethnicity in England, but results were negative. The lack of variation in the incidence of ALL among ethnic groups in England, in conjunction with the markedly lower incidence of ALL in the Indian subcontinent and Africa than in England, suggests that the incidence of ALL depends to some extent on environmental factors in association with geographic location. The contrast between the ethnic variations in incidence could be a reflection of the socioeconomic differences by ethnicity (or the lack thereof) in the two countries. A recent report from the Malaysia-Singapore Leukemia Study Group describes differences in prognostically important chromosomal abnormalities among an unselected multiethnic Asian population. Ethnic groups differed significantly with regard to the proportion of patients with ALL who had T-cell ALL (the incidence is higher in Chinese and Indians), ETV6-RUNX1 (with a lower incidence in Chinese persons), and BCR-ABL (with a lower incidence in Indian persons). Beyond ethnic differences in the occurrence of childhood ALL, it has been well documented that race/ethnicity is associated with prognosis. The black-to-white ratio of the incidence of AML in the United States is 0.85. The rates are highest among Hispanics. This higher rate of AML contributed to the higher incidence of acute promyelocytic leukemia seen among Hispanics than among non-Hispanics, thus raising the question of genetic predisposition to acute promyelocytic leukemia or exposure to distinct environmental factors. As with ALL, race/ethnicity also has prognostic importance.

Socioeconomic Status

Socioeconomic factors have been proposed as an explanation for the age peak in childhood leukemia. Thus it has been hypothesized that with economic development, poorer communities move from a situation in which leukemia is rare (T-cell ALL is the predominant type of ALL) through an intermediate stage in which cALL begins to appear to a state of high socioeconomic status that is associated with a high incidence of ALL and cALL. Numerous descriptive studies have investigated the relationship between leukemia and socioeconomic status. In the vast majority of these studies, the area of residence of the patients (or those who died) was used as a measure of socioeconomic status. Other measures used included household income and years of schooling. In most of these studies, a weak positive association between leukemia and high socioeconomic status was observed, with a few exceptions. In contrast, several investigators have examined the relationship between AML and socioeconomic status and have failed to show an association.

Time Trends

Several investigators have examined temporal trends for leukemia, but the findings are difficult to interpret, primarily because of the varying periods covered and different methods of analysis used. Some investigators analyzed the 0- to 14-year-old age group as a whole, whereas others examined trends in specific age groups. Some investigators reported trends for each sex, whereas others combined the two sexes in their analyses. In some analyses all leukemias were grouped together, whereas others conducted their analyses by the leukemia subtype. In addition, diagnostic improvements have led to more accurate and precise classification of leukemias over time, which could contribute to the observed temporal trends in incidence.

In the studies reporting an increase in the incidence of ALL, the increase is fairly modest and is confined to the 0- to 4-year-old age group. Moreover, in some reports, the increase in incidence of ALL appeared to be accompanied by a decrease in the incidence of AML or other leukemias, which could reflect diagnostic shifts and more accurate and precise classification. A temporal increase in the incidence of childhood ALL has been reported in England and is attributed to an increase in the precursor B-cell subtype. Between 1974 and 2000, the average annual increase in childhood ALL was 0.7% overall but 1.4% for cALL. Similarly, analyses of childhood ALL time trends in Italy demonstrated increases, some of which were related to maternal time variables that included maternal age and maternal birth cohort, which were considered to be consistent with an infectious cause. On the other hand, in another study, Linet and associates report no substantial change in the incidence of childhood leukemia diagnosed in the United States between 1975 and 1995. The Czech national registries reported a 1.5-fold increase in childhood ALL incidence between the ages of 1 to 4 years during the period of substantial socioeconomic transition in the European postcommunist countries.

Clustering of Leukemia in Space and Time

Spatial clustering of childhood leukemia has been observed to varying degrees in England, France, and Greece but not in the United States. Where spacial clustering was identified, it was strongest for leukemias diagnosed in younger children. Although spatial clustering was confined to sparsely populated areas in England, such clustering was found only in urban areas in Greece. Birch and colleagues addressed the issue of space-time clustering by using the Manchester Children’s Tumor Registry. All methods showed highly significant evidence of space-time clustering on the basis of place of birth and time of diagnosis of childhood leukemia. The authors concluded that the results were consistent with an infection hypothesis (discussed later). Furthermore, the investigators found an excess of instances in males versus females in space-time pairs, thus suggesting gender-specific susceptibility to infections. More recently they have reported statistically significant cross-clustering among childhood leukemia and central nervous system (CNS) tumors and between ALL and astrocytoma, suggesting possible common causes, possibly of an infectious nature. The correlation between childhood leukemias and CNS tumors is of interest, given the recently reported correlation in international rates for these two pediatric cancers.

Historically, clusters of childhood leukemia have been observed in which the number of cases reported exceed those expected within a given time and geographic location. Investigation of these clusters has typically not identified any causal agent. A recent leukemia cluster in the United States gained substantial public and scientific attention because of the marked excess observed within a small population. Comprehensive investigation including biologic samples from persons within the population that were analyzed for chemicals, viral markers, and genetic polymorphisms, in conjunction with air, water, soil, and dust sampling, failed to identify any leukemia risk factor.

Concordance of Childhood Leukemia in Twins

Assessment of concordance for childhood leukemia in twins may provide etiologic clues. If childhood leukemia were to have a predominantly genetic cause, monozygotic twins would be expected to be concordant for leukemia more often than dizygotic twins because of their genetic similarity. If childhood leukemia were caused by an abnormal intrauterine environment, it would be expected that if one member of a dizygotic twin pair were affected, the other twin would be affected more often than a nontwin sibling because of the shared environment. Recently, in a study of leukemia in a pooled series from the United States, Canada, and England, only three concordant pairs (1.5%) were found among 197 pairs in which one or both twins had leukemia, with the concordance rate for monozygotic twins reported to be 3.9% (95% confidence interval [CI], 0.8 to 11.1). Although the concordance rate in twins of like sex (probably monozygotic twins) is higher than the zero concordance rate reported for twins of unlike sex (dizygotic twins), the concordance rate in twins of like sex is quite variable. These findings suggest that inherited genetic factors most likely play a relatively small part in the cause of childhood leukemia.

The occurrence of concordant leukemic pairs has been hypothesized to be due to parallel expansions of clones descended from a single, ancestral cell transformed in utero, with a malignant clone arising in one monozygotic twin and entering the circulation of the co-twin through anatomizing placental vessels. This mechanism would account for the early and similar age of onset of leukemia and the similar cytogenetic findings. Support for this hypothesis is provided by the recent observation of shared clonal but nonconstitutional mixed lineage leukemia gene ( MLL) rearrangements in the leukemic cells of three pairs of monozygotic twins concordant for infant acute leukemia. The rearrangements were not observed in nonleukemic cells of the twins and were not present in the maternal or paternal blood of two of the three twins.

Leukemia and Cancer in the Families of Children with Leukemia

In studies of leukemias of all types combined, no excess of cancer was observed among siblings, parents, or offspring. In studies focusing on acute leukemia, an excess of acute leukemia was observed among siblings, in whom the expected rates were extremely low. Limitations of these studies include the inclusion of distant relatives, in whom verification of cancer becomes problematic, incomplete follow up, and, finally, the inclusion of families with a history of consanguinity.

Cancer in Offspring of Patients Treated for Childhood Leukemia

Few studies have reported the rate of occurrence of cancer in the offspring of patients treated for childhood leukemia. Only recently have enough patients survived that the number of their offspring permitted estimates of their risk of developing malignant neoplasms. After performing a review of the literature, Hawkins and associates estimated that the proportion of heritable cases among survivors is unlikely to exceed 5%, assuming that the age of onset of all heritable cases is 15 years of age or younger and that the diseases had a penetrance of 70% or more. Chromosomal instability was examined in 20 apparently healthy children of survivors of childhood malignancy. Compared with control subjects, no increases in spontaneous or bleomycin-induced aberrations were found in these “index children.” The results suggest that the offspring of subjects who previously received chemotherapy, radiotherapy, or both for childhood malignancy probably have no increased risk of latent chromosomal instability.

Other Conditions in Relatives of Patients with Leukemia

Savitz and Ananth reported an excess of major birth defects among the siblings of patients with ALL (relative risk [RR], 3.2; 95% CI, 1.3 to 7.7; adjusted for age at diagnosis, sex, and year of diagnosis). Mann and colleagues reported an excess of congenital defects among parents, uncles, aunts, and other distant relatives of patients with ALL compared with community control subjects. Buckley and associates reported an excess of a number of conditions in siblings, parents, and grandparents of index patients with various types of ALL. These conditions included musculoskeletal disorders among relatives of patients with the common cell type; gastrointestinal, hematologic, and musculoskeletal disorders and allergies for those with the pre–B-cell type; an excess of gastrointestinal disorders for those with the T-cell type; and an excess of congenital heart and lung disease for those with the null cell type. The offspring of adult survivors of childhood ALL were not found to have an increased risk of occurrence of congenital anomalies compared with the offspring of sibling control subjects. Similarly, Kenney and colleagues reported no excess of congenital anomalies among the offspring of adult survivors of childhood cancer compared with the offspring of sibling control subjects.

Human Leukocyte Antigen–DR and Susceptibility to Childhood ALL

Both genetic and environmental factors could possibly play an interactive role in the development of childhood ALL. Because of the demonstration of the influence of major histocompatibility complex on mouse leukemia, a human leukocyte antigen (HLA) association has been considered as a possible genetic risk factor. Dorak and associates demonstrated a moderate association with the most common allele in the HLA-DR53 group, HLA-DRB1*04, which was stronger in males. In addition, homozygosity for HLA-DRB4*01, encoding the HLA-DR53 specificity, was increased among patients. Confounding these associations was a male-specific increase in homozygosity for HLADRB4*01. The cross-reactivity between HLA-DR53 and H-2Ek, extensive mimicry of the immunodominant epitope of HLA-DR53 by several carcinogenic viruses, and the extra amount of deoxyribonucleic acid (DNA) in the vicinity of the HLA-DRB4 gene provide arguments for the case that HLA-DRB4*01 may be one of the genetic risk factors for childhood ALL. Comparison of DQA1 and DQB1 alleles in 60 children with ALL and 78 newborn infants (control subjects) revealed that male but not female patients had a higher rate of occurrence of DQA1 *0101/*0104 and DQB1 *0501 than did appropriate control subjects. The authors concluded that this finding represented a male-associated susceptibility haplotype in ALL, supporting an infectious cause. Additional investigations from the United Kingdom have suggested that cALL in children may be associated with HLA-DPB1 through a mechanism that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, which leads to activation of helper T cells that mediate proliferative stress on preleukemic cells.

Susceptibility to Childhood ALL: Genetic Polymorphisms

In the search for gene-environment interactions in the cause of childhood leukemia, investigations have focused on the genetic variability in xenobiotic metabolism, DNA repair pathways, and cell-cycle checkpoint functions that might interact with environmental factors to influence leukemia risk. Although much of the research in this area has been limited by small sample size, data suggest a potential role for polymorphisms in genes encoding cytochrome P450, glutathione S-transferase, reduced nicotinamide adenine dinucleotide phosphate quinone oxidoreductase, methylenetetrahydrofolate reductase (MTHFR), cycle-cycle inhibitors, and DNA-repair polymorphisms.

In general, few reports have addressed the potential role of these polymorphic genes in childhood leukemia, and in many instances they provide contradictory findings. This situation is particularly true with regard to studies of GSTM1 and GSTT1 and CYP-P450 enzymes. Low folate intake or alterations in folate metabolism as a result of polymorphisms in the enzyme MTHFR have been associated with neural tube defects and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. Wiemels and colleagues and Smith and colleagues reported an association of MTHFR polymorphisms in infant leukemias with MLL gene rearrangements and childhood leukemia with either ETV6-RUNX1 fusions or hyperdiploid karyotypes. These studies provide evidence that molecularly defined subgroups of childhood leukemias may have different causes and also suggest a role for folate in the development of childhood leukemia. In a case-control study, MTHFR genotypes TT677/AA1298 and CC677/CCC1298 were associated with a reduced risk of childhood ALL. Moreover, the findings of these studies suggested a gene-environment interaction based on timing of implementation of folic acid supplementation in the Canadian population. To date, no direct gene-environment associations have been established convincingly. When considering the potential importance of the prenatal origin of childhood leukemia, it becomes important to consider the genotypic profile of the mother with respect to metabolizing enzymes. Investigation of maternally mediated genetic effects through reduced nicotinamide adenine dinucleotide phosphate quinone oxidoreductase did not affect risk for childhood ALL.

The Kinlen Hypothesis: Residence in Areas with High Population Mixing

In 1988 Kinlen hypothesized that the high incidence of leukemia in children in the vicinity of the Sellafield and Dounreay nuclear reprocessing plants in England could be due to a rare response to some unidentified mild and subclinical infection, the transmission of which is facilitated by contacts between large numbers of people. An influx of people of diverse origin into a previously isolated area would particularly facilitate transmission. Thus a high incidence of leukemia in childhood would be expected in isolated areas into which a significant influx of people had occurred. The hypothesis was first tested in an area in Scotland. Glenrothes New Town was identified a priori as an area where, after a period of relative isolation, a sudden burst of in-migration occurred in 1964 because of the opening of the Forth Road bridge. A significant number of persons younger than 25 years who died of leukemia were identified during the period from 1951 to 1967. The incidence of leukemia was not excessive in the period from 1968 to 1985, when the community became much less isolated. The hypothesis has been tested in a number of other situations in England, France, and other parts of Europe and Hong Kong. * A 3.6-fold increase in childhood leukemia was observed in the wartime cohort compared with national Scottish rates in Orkney and Shetland (England’s northernmost islands) during World War II, when the local people were outnumbered by servicemen stationed there. The rates normalized to the national rates in the postwar period. A recent analysis of the U.S. Surveillance Epidemiology and End Results data also provided confirmatory evidence for the population mixing hypothesis, with findings that changes in rural county population sizes from 1980 to 1989 were associated with increased incidence rates for childhood ALL.

* References .

Infections during the Index Pregnancy

An alternative model for the cause of childhood ALL places the critical infectious event during pregnancy rather than early childhood. In this model, the etiologic agent causing the primary infection in the mother is transmitted to the fetus, and as a consequence of this in utero infection, the child is at increased risk for the development of ALL before the age of 5 years. The characteristics that the causative infectious agent should possess include: (1) the ability to induce genomic instability, (2) specific effects on B lymphocytes and not on T lymphocytes, (3) higher rates of infection in regions with lower socioeconomic status, (4) limited general oncogenic potential, (5) minimal symptoms associated with the primary infection, and (6) the ability to cross the placenta and infect the fetus but not result in severe fetal abnormalities. A virus that meets several of these criteria is the JC virus, a member of the polyomavirus family.

The possibility that maternal infection during pregnancy could potentially be leukemogenic is supported by the observation that leukemia in cats is caused by a feline virus transmitted from the mother to the fetus. Three cohort studies of maternal infection during pregnancy and subsequent childhood cancer revealed an excess of cancer in these children compared with the age- and sex-matched general population. In case-control studies, no association between maternal infection with influenza or varicella and subsequent childhood cancer was seen. With regard to maternal infection in general, a twofold excess of childhood cancer has been reported. However, the studies are small or the reported prevalence of exposure is low and may be attributed to recall bias. Neonatal blood spots have been used to identify evidence of selected in utero viral infections. Investigation of cytomegalovirus and human parvovirus B19 infection failed to identify DNA in the small groups of childhood ALL cases compared with healthy control subjects. First-trimester serum samples from mothers of children diagnosed with ALL derived from large maternal cohorts in Finland and Iceland have been tested for antibodies to Chlamydia trachomatis , Helicobacter pylori, and Mycoplasma pneumonae. Comparison of ALL cases to control subjects identified an increased risk associated with M. pneumoniae immunoglobulin M and, in Iceland, H. pylori immunoglobulin G. Within the same maternal cohort, evidence was found for activation of maternal Epstein-Barr virus infection in both childhood ALL and non-AML cases.

Smith and colleagues sought to assess the relationship of childhood ALL with hygiene conditions, an aspect of socioeconomic development affecting rates of exposure to infectious agents. The data suggested that improved public hygiene conditions measured by decreased prevalence of hepatitis A virus infection (an agent with a fecal-oral route of transmission) were associated with high childhood ALL incidence rates. The model presented in this study supports the plausibility of the hypothesis that decreased childhood exposure to a leukemia-inducing agent associated with hygiene conditions leads to higher rates of ALL in children by increasing the incidence of in utero transmission caused by primary infection during pregnancy (or by increasing the number of persons infected in early infancy because of a lack of protective antibodies).

Antibiotic Use and Immunizations during the Index Pregnancy

No association between antibiotic use during pregnancy and leukemia has been identified. No consistent association has been reported between vaccination during pregnancy and leukemia. Salonen and Saxen found a positive association between leukemia and maternal polio vaccination during pregnancy. Similarly, Gilman and associates reported a positive association between total childhood deaths and vaccination during pregnancy that was largely accounted for by neoplasms of the reticuloendothelial system. However, results of a population-based study in the Netherlands showed no association between vaccination during pregnancy and ALL.

Association of Childhood Leukemia with Factors Related to the Immune System

It has been proposed that some instances of pediatric ALL arise as a rare response to a common childhood infection and that the leukemia-inducing potential of the agent is related to the timing of infection, with a greater leukemogenic effect for later infections compared with those occurring during infancy. In this context, factors related to the child’s immune system are of special interest. Several investigators have sought to identify factors such as birth order and breastfeeding that can potentially be used as markers of infections or confer protection against infection before the diagnosis of leukemia.

Radiation Exposure

In utero exposure to radiation has been reported to be associated with a small yet statistically significant increased risk of development of childhood leukemia in numerous case-control studies. ^† Reported estimated risks generally ranged from 1.1 to 2.0, with most of the risk ratios being equal to or lower than 1.6. It is reasonable to expect that in utero levels of exposure to radiation would have declined substantially over time given the knowledge of health-related risks associated with radiation exposure and the reduced level of radiation required for diagnostic procedures. Studies from Sweden, England, and the United States have demonstrated higher risk estimates among children born in earlier eras (e.g., the 1930s to 1950s) compared with more recent periods. Nonetheless, the potential role of in utero exposure to radiation in childhood leukemia has remained controversial. Much of the debate has focused on the lack of an observed association among offspring of mothers who were exposed while pregnant at the time of the Hiroshima and Nagasaki atomic bombs coupled with concerns regarding the lack of good exposure assessment and the potential for recall bias in case-control studies of the topic. Results from a large case-control study in North America did not identify an overall increased risk associated with in utero pelvimetric diagnostic x-rays or associations within subgroups defined by immunophenotype. It is likely that the reduced rate and dose of exposure in North America has resulted in an inability to detect the small risk that may exist.

† References .

A number of investigations of environmental exposures of children to sources of radiation from nuclear detonations and power plants were conducted to determine the potential impact on leukemia risk. In studies of children who survived the atomic bombs of Hiroshima and Nagasaki, an increased occurrence of leukemia 5 to 15 years later was seen. Leukemia risk was positively correlated with the dose of radiation among the atomic bomb survivors. Reports relating to follow-up of nuclear accidents at Three Mile Island and early reports from Chernobyl did not provide strong evidence of an increased risk of childhood leukemia. Analyses that included residents in the area surrounding the Three Mile Island facility did not reveal an increase in the ratio of observed to expected incidence of leukemia. Similarly, investigation of specific regions of the former Soviet Union did not reveal increased rates of childhood leukemia within the first 5 years after the Chernobyl accident. Because of the widespread fallout from Chernobyl, a series of investigations were undertaken in affected countries, including Sweden, Finland, England, Scotland, Germany, and Greece. With the exception of higher rates in Scotland and an observed excess of infant leukemia (i.e., in children younger than 1 year) in Greece, results were generally negative for an observed increase after the accident. The most recent investigation of the acute and long-term risks for childhood leukemia resulting from radiation exposure (a median estimated dose of <10 mGy) after the Chernobyl power station accident identified a significant increase in leukemia risk with increasing radiation dose to the bone marrow. However, the potential overestimate of childhood leukemia risk within one region raised serious concerns about conclusions that could be drawn with regard to the level of risk resulting from the Chernobyl accident.

During the 1950s, testing of nuclear weapons took place in Nevada, with nuclear fallout affecting regions of Nevada and Utah. Studies were carried out in Utah to determine the potential impact on childhood leukemia, using geographic region–specific radiation dose estimates to the bone marrow. No significant trend between estimated dose and risk of leukemia mortality was found. However, the risk of death from leukemia was found to be higher in those exposed at the highest dose level (6 to 30 mGy) compared with those in the lowest dose group (0 to 2.9 mGy).

During the past several decades, the potential impact of nuclear facilities, either nuclear energy plants or nuclear reprocessing plants, has generated considerable interest with regard to cancer risk among surrounding residents. Studies addressing childhood leukemia have been conducted in England, France, the United States, Germany, and Canada. In aggregate, these investigations have not provided strong evidence of an increased occurrence of childhood leukemia, although several have reported increases in incidence and mortality.

Although the biologic plausibility of indoor radon exposure and the cause of childhood leukemia are speculative and debatable, studies have been conducted to address the topic. Although ecologic investigations have provided some evidence for a correlation, case-control studies incorporating measurement of indoor radon levels have not found higher levels within homes of children with ALL or AML.

Parental Occupational Exposures

Occupational exposure of parents and its association with childhood leukemia have been the subject of several investigations. Occupations and exposures of fathers were investigated more often than were those of the mother. Detailed assessment with use of a job exposure matrix to classify occupational exposures identified an increased risk for childhood AML in association with maternal exposure to 1,1,1-tricholorethane, toluene, mineral spirits, alkanes, and mononuclear aromatic hydrocarbons, although dose-response associations were not present. Exposure in the home was not associated with increased risk. Investigation within the UKCCS identified small but statistically significant increased risks among children with ALL whose fathers reported their occupation to involve motor vehicle driving and were exposed to exhaust fumes and/or inhaled particulate hydrocarbons. The studies have several limitations related to the quality of exposure assessment, small numbers of exposed children, multiple comparisons, and possible bias toward the reporting of positive results. Although some evidence exists for an association between childhood leukemia and paternal exposure to solvents, paint, and employment in motor vehicle–related occupations, clearly established associations between parental occupation and childhood leukemia are lacking.

Exposure to Chemicals and Dust

Electromagnetic and Radiofrequency Field Exposure

An initial report in 1979 suggested an association between childhood leukemia and residential proximity to sources of electric and magnetic fields, as assessed by wiring configurations. Subsequently, a large number of investigations have been conducted to further evaluate the hypothesis that exposure to extremely low-level electric and magnetic fields may influence the risk of childhood leukemia and other pediatric malignancies. ^‡ These studies, although they provide some consistent findings, are difficult to interpret given the inconsistencies observed in associations between inferred exposure (i.e., wire configuration) compared with measured fields.

‡ References .

Although not as extensively studied as electric and magnetic fields, radiofrequency exposure has been suggested as a possible cancer-related risk factor. A recent report investigating radiofrequency exposure in 1928 patients with childhood leukemia observed a twofold risk associated with living within 2 km of an amplitude modulation radio transmitter, which was statistically significant in a dose-dependent fashion for childhood ALL.