What do we already know?

It is true that we still do not know for sure why our children get cancer. Scientists are also asking the same questions. It is generally believed that the childhood cancer is caused by a complex interaction of genetic and environmental factors that the scientists do not fully understand yet. As numerous studies have been made to detangle the complex nature of cancer, it is becoming more evident that certain environmental and genetic factors may only affect cancer when combined. Environmental factors are normally examined in population-based studies. Due to the limited evidence or inconclusive results, researchers are giving great focus on the gene-environment interaction studies - this is where they investigate some genetic variants that may cause cancer when they are combined with specific environmental exposures, which otherwise may not be risk factors for childhood cancer.

Although it is difficult to unravel the environmental factors causing childhood cancer in population studies it does not mean that we have to stop such studies. Population studies give us clues on where to focus our detailed clinical research.

There are several well-established environmental causes of childhood cancer. The earliest known exposures were radiation, diethylstilbestrol and some chemotherapeutic agents. The studies of Japanese children who were exposed to atomic bomb radiation have found that these children, as they grew, had higher rates of childhood leukaemia than unexposed children. Many other agents such as electromagnetic fields, pesticides and some parental occupational exposures are suspected of playing roles, but the evidence is not yet conclusive.

Below is the list of potential causes that researches have studied to date. We have divided these studies into three time periods.

Parental occupational/non-occupational exposures to environmental agents leading to genetic abnormalities

Research so far includes:

  • Pesticides [Daniels, 1997; Zahm & Ward, 1998; Van Maele-Fabry, Lantin, Hoet & Lison, 2010]
  • Carbon related jobs, e.g., paint, benzene, wood dust and radiation exposure [Kwa & Fine, 1980; Sanders, 1981; Arundel, 1986; Savitz & Chen, 1990; McKinney, 1991; Colt & Blair, 1998; Peters et al., 2013]
  • Recreational use of drugs, e.g., marijuana and cocaine [Tashkin, 2001; Hall & MacPhee, 2002]
  • Parental smoking and alcohol consumption [Milne et al., 2013]


Some studies report associations between childhood cancer and parental exposure to pesticides. These studies suggest an increase in risk of brain tumour, leukaemia, non-Hodgkin lymphoma, Wilm's tumour, and Ewing's sarcoma and germ cell tumours associated with parental occupational and non-occupational exposure to pesticides.

A systematic review and meta-analysis published in 2010 reported that no statistically significant association between childhood leukemia and parental occupation as farmers/agricultural workers was observed. However, significant increased risks were seen for paternal exposure.

Carbon related jobs

Associations between hydrocarbon related parental jobs and CNS tumours, and between paint, benzene, wood dust and radiation, diesel exhaust exposure of parents and leukaemias have also been reported.

Recreational use of drugs

Possible associations were reported between recreational use of drugs such as marijuana and cocaine, and leukaemia and lymphoma.

Smoking and Alcohol before pregnancy

It is reported that parental smoking before or during pregnancy showed no association with the risk of childhood brain tumors (CBT). Although tobacco increases the risk of several adult cancers, the cause of CBT remains largely unknown.

Further, there is no evidence that maternal alcohol use before or during pregnancy were associated with an increased risk of either cancer; rather, there was evidence of inverse associations, particularly with wine. For both cancers, negative associations were observed with paternal alcohol consumption in the year before the pregnancy, possibly driven by reduced risk at moderate levels of beer and wine intake and increased risk associated with high levels of beer intake. Moderate intake of spirits by fathers was associated with an increased risk of childhood brain tumors (CBT) but not acute lymphoblastic leukemia (ALL).

Maternal exposure to environmental agents during pregnancy

Research so far include:

  • Dietary exposure to N-nitroso compounds [Rice et al., 1989; Kuijten, 1990; McCredie, 1994; Peters, 1994; Preston-Martin, 1996; Blot et al, 1999; Bunin GR, 2000; Pogoda & Preston-Martin, 2001; Huncharek, 2004]
  • Dietary exposure to bioflavonoids [Ross, 1994; Ross, 1996; Spector, 2005]
  • Dietary or direct exposure to diethylstilbestrol (DES) [Herbst, 1971, 1977, 1981, 1999; Gill, 1976, 1977; Depue, 1983; Niculescu, 1985; Anderson, 2000]
  • Tobacco smoking, alcohol consumption and recreational use of drugs by parents [Sasco & Vainio, 1999; Little, 1999]
  • Anemia [Roman, 2005;UKCCS]
  • Infections [Smith, 1997, 1998; Magrath et all., 2013]
  • Intrauterine growth and pregnancy events [O'Neill, Bunch & Murphy, 2012; Musselman et al., 2013]
  • Genital herpes, blood and immunological disorders during pregnancy [Oksuzyan, Crespi, Cockburn, Mezei & Kheifets, 2013]

Dietary exposure to N-nitroso compounds

Animal studies have shown that N-nitroso compounds are powerful carcinogens to be able to pass placenta to the developing fetus. They are considered to be risk factors for certain adult cancers. It is hypothesised that these compounds synthesised from relevant food stuffs (e.g., excessive hot dog and cured meat consumptions) ingested by mothers during pregnancy might act as carcinogens passing through the placenta and that a high intake of fruit and vegetables or vitamin C supplements may play protective roles. This hypothesis has been tested in a number of studies focused on childhood brain tumours. The studies reported an association between these compounds during pregnancy and subsequent childhood brain tumour in offspring. It is also implied in childhood leukaemia.

Dietary exposure to bioflavonoids

Flavonoids, referred as bioflavonoid in media, are commonly known for their antioxidant activity. Good dietary sources of flavonoids include all citrus fruits, berries, onions, parsley, green tea, red wine and dark chocolate. Some of these flavonoids, known as DNA topoisomerase (DNAt2) inhibitors, have been shown to cause site-specific DNA cleavage in the MLL gene breakpoint cluster region on chromosome 11q23. It has been, therefore hypothesised that the infant leukaemias (of which 80% have the MLL abnormality) may occur as a result of maternal exposure to flavonoids in diet during pregnancy and medications that inhibit DNAt2. Contradictory associations have been reported in various studies.

Dietary or direct exposure to diethylstilbestrol (DES)

DES is a synthetic non-steroidal oestrogen drug that was first synthesized in 1938. In 1971, it was found to be a teratogen (refers to disfiguring birth defects or malformation) when given to pregnant women. During the 1960s, DES was used as a growth hormone in the beef and poultry industry. It was later found to cause cancer and was phased out in the late 1970s. Studies demonstrated that cancer could be induced by DES passing through the placenta. Another study found that DES could be trans-generational meaning that the third generation may be effected by the DES used by the maternal grandmother.

Tobacco smoking, alcohol consumption and recreational use of drugs by parents

Animal studies provided evidence that some genotoxic and carcinogenic compounds can pass placenta to the developing fetus. Because of this it is hypothesised that exposure to these agents during pregnancy is a risk factor for childhood cancers. However, no consistent associations were reported between maternal exposures to these agents and childhood cancers.

Studies did not find any consistent association between maternal tobacco smoking during pregnancy and any type of childhood cancer. Possible association has been reported between paternal smoking and ALL. Positive association has been reported between maternal alcohol consumption during pregnancy and AML.


It has been reported that there is an increased risk for AML with anemia detected during pregnancy. It has been also reported that anemia should be examined along with other factors.


ALL has been attributed to an infectious exposure of the fetus during the pregnancy but no evidence has been found to support this theory.

It is reported that low-income and middle-income countries have younger populations and therefore a larger proportion of children with cancer than high-income countries. Also, chronic infections, which remain the most common causes of disease-related death in all except high-income countries, can also be major risk factors for childhood cancer in poorer regions.

Intrauterine growth and pregnancy events

A series of reports illustrate a convincing link between the rate of intrauterine growth and the risk of childhood leukemia. Some studies suggest that this risk relationship also extends to non-Hodgkin lymphoma in children, although, overall, the association with childhood lymphoma is less clear.

It is reported that risk of hepatoblastoma was significantly associated with maternal first trimester weight gain and nearly significantly with maternal multivitamin use. Hepatoblastoma was not associated with other maternal weight changes, maternal illness or medication use during pregnancy.

Genital herpes, blood and immunological disorders

It is suggested that maternal genital herpes, blood and immunological disorders during pregnancy and newborn CNS abnormalities were associated with increased risk of CNS tumors. Maternal infections during pregnancy were associated with decreased risk of CNS tumors. Advanced maternal and paternal ages may be associated with a slightly increased risk of CNS tumors. Factors associated with CNS tumor subtypes varied by subtype, an indicator of different etiology for different subtypes

Child's direct exposure to environmental agents

Children are not simply small adults. The major difference between children and adults is the fact that children are developing and growing. Exposures to environmental agents can result in more profound consequences in a child, than a similar exposure in an adult. These environmental agents may results in mutations in genes involved in control of cell division, apoptosis (programmed cell death), growth and differentiation. Infants and children differ from adults in their exposure both qualitatively and quantitatively. They eat more food, drink more water and breathe more air per unit of body weight than adults do, and the activity patterns of children further increase their exposure to environmental agents.

  • Atmospheric pollution [Knox, 2005]
  • Electric and magnetic fields [Wertheimer & Leeper, 1979; Wartenberg D, 1998, 2001; UKCCS, 1999; Draper, 2005; Kheifets, Afifi, Monroe, Swanson, 2011]
  • Radon exposure [Tong et al., 2012]
  • Pesticides [Daniels, 1997; Landrigan, 2003]
  • Residing near nuclear power plants [Ghirga, 2010; Fairlie, 2010]
  • Atopic diseases [Wen, 2000; Manning & Carroll, 1957]
  • Infections [McKinney, 1987; Dockerty, 1999; Nyari, 2003; Cope, 2000; Dorak, 1996; Kerr, 2003; Priftakis, 2003; MacKenzie, 1999; Smith, 1999; Little J, 1999; Metayer et. al., 2013]
  • Blood levels of folate at birth [Chokkalingam et al., 2013]
  • Theories:
    • Population mixing [Kinlen, 1995; Alexander, 1997; Boutou, 2002]
    • Two-independent mutations [Greaves & Alexander, 1993]
    • Seasonality [Badrinath, 1997; Feltbower, 2001; Karimi & Yarmohammadi, 2003]
    • Pre-school day care [Dockerty, 1999; Neglia, 2000; Gilham, 2005]
    • No or little breastfeeding [Schuz, 1999; Bener, 2001; Martin, 2005]
    • Clustering [McNally, 2002; Greenberg & Shuster, 1985; Schmidt, 1998; Alexander, 1999]

Atmospheric pollution

A recent study in the UK reports associations to childhood cancer development with proximity of birth places to sites of industrial combustion, volatile organic compounds (VOCs) uses and associated engine exhausts, 1,3-butadiene, dioxins and benz(a)pyrene.

Electric and magnetic fields

Electromagnetic fields create low frequency non-ionising radiation which can cause molecular damage. Electromagnetic fields include static fields, power frequency fields, radio frequency fields and UV radiation. These fields are everywhere in modern societies. Examples of sources of exposure are production and use of electric power, electronic surveillance systems, wireless communications, tanning machines and solar exposure. The most visible source to extremely low frequency (ELF) magnetic fields is arguably power lines and in particular high voltage transmission lines. It was first pointed out in 1979 that long term-term exposure to low frequency magnetic fields (e.g., living near the power lines) may be associated with leukaemia risk in children. Further studies concluded that the data supporting residential electromagnetic fields as the principle risk factor are suggestive with small to moderate effect sizes. A study carried out in the UK in 1999 showed a trend of increasing incidence with increasing exposure but the study was not powerful enough to provide a statistically significant result. Recently, in a large case-control study it was concluded that a child’s risk of leukaemia increased steadily with proximity to high voltage power lines of the home they lived in at birth and the distance up to 600m may increase the risk.

It is now internationally agreed that the electric and magnetic fields are a possible cause for concern in humans.

An article published in 2011 reports that extremely low frequency magnetic fields such as those are produced by electric power systems may not be associated with elevated risks of childhood leukemia.

Radon Exposure

Although leukemia can be induced by Radon, it has not been consistently demonstrated. It is reported that by applying a meta-analysis, an increased risk of childhood leukemia induced by indoor radon exposure was noted for overall leukemia and for acute lymphoblastic leukemia (ALL)

Residing near nuclear power plants

It is reported that among children living within 5 km of all German nuclear power stations, there is an increased risk of cancer incidence. The article also outlines a possible biological mechanism to explain the increased cancers, suggesting that doses from environmental nuclear power plant emissions to embryos/ fetuses in pregnant women near the plants may be larger than suspected, and that hemopoietic tissues may be considerably more radiosensitive in embryos/ fetuses than in newborn babies.

It is also reported that children under five years of age living near nuclear power plants (NPPs) had an increased risk of cancer incidence. Nevertheless, other UK, France, Spain and Finland studies did not find cancer incidence and/or death increase near NPPs.


Associations between a child’s exposure to pesticides and childhood cancer have been reported. Certain pesticides are classified as endocrine disruptors and linked to childhood cancer development.

Atopic diseases

Studies showed contradictory associations between asthma and other allergic diseases, and leukaemia, neuroblastoma and lymphoma.


Researchers suspected that infections can be a risk to children to develop cancer. There is some evidence supporting an infectious aetiology for childhood leukaemia, particularly c-ALL but the agents involved and the precise mechanisms are unclear. Studies mainly focused on early year (birth to 12 months) exposures to certain viruses which included influenza, measles, CMV, adenovirus, parvovirus, polyomavirus-JCV, polyomavirus-BKV, polyomovirus-SV40, herpes virus, HHV-6 virus, chicken pox and mumps. The only common feature of these studies is the lack of consistency.

There is weak evidence for the involvement of infections in childhood tumours. Some studies suggest an infectious aetiology for at least some CNS tumours and osteosarcomas.

On the other hand, there is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood acute lymphoblastic leukemia (ALL).

Blood levels of folate at birth

It is reported that there is no association between birth folate concentrations and risk of childhood acute myeloid leukemia (AML) or major acute lymphoblastic leukemia (ALL) subgroups. Impact: However, they do not rule out a role for folate through exposures after birth or in early stages of fetal development.


There are various theories for the origin of infections focusing mainly on leukaemia:

Population mixing: It has been suggested that in areas where there is an influx of residents from other areas there would be an increased level of contacts between susceptible individuals and infected individuals (impaired herd immunity hypothesis). Non-exposed individuals living where the relevant infection is not endemic, subsequently become at risk when exposed by mixing with an incoming population of infected carriers. This hypothesis has been tested in the UK. Studies indicated an increased risk of ALL in such mixed populations. It is suggested that one or more specific agents are involved.

Two-independent mutation: It has been suggested for the common subtype of ALL (c-ALL) arises as a result of two independent mutations. The first (creation of pre-leukaemic clone of cells) is occurring during the pregnancy or soon after birth. The second mutation occurs after an average period of three years leading to onset of disease. It has been suggested that common childhood diseases can serve as a promoter of the second mutation. Therefore, if there is a delay in the normal pattern of exposure of the child’s immune system to common childhood infections, this delay may increase the number of susceptible cells hence increasing the risk of the second mutation. Delay in the child’s exposure to common infections might occur due to lifestyle changes associated with socio-economic development (delayed infection hypothesis). This hypothesis considers infections in general.

Seasonality: Seasonality of onset has been shown for ALL, which is presumed to be characteristics of infectious diseases.

Pre-school day care: Children are generally at risk of getting infectious diseases if they attend day care at an early age. This can be considered protective as well. No evidence has been reported to show any associations between day care attendance and leukaemia.

No or little breastfeeding: It has been reported that breastfeeding has great benefits to the infant as well as the mother. These include health, nutritional, immunologic, developmental, psychological, social, economic, and environmental benefits. Therefore, it has been hypothesised that no or perhaps little breastfeeding of the infant should expose the infant to infections by eliminating the protective effects, particularly immune stimulation, of breastfeeding. However, some studies found no or weak protective associations with childhood leukaemia whereas some others found a small but significant protective effect of breastfeeding for ALL, Hodgkin’s lymphoma and neuroblastoma.

Clustering: Researchers have been concerned for many years by the existence of clusters of childhood cancer cases, particularly of leukaemia. Hypothesis was that the clusters might point to an infectious origin to localised environmental exposures. The strongest clusters have been observed for children with leukaemia diagnosed before six years of age in the UK. However, no known cause for clustering has been identified. Speculations included population mixing and environmental pollution. It should be remembered that the clustering does not mean cases diagnosed simultaneously as in an infectious disease outbreak. Evidence for the involvement of infections in childhood tumors is weak. However, space-time clustering among childhood CNS tumors in the UK has been reported. This could support an infectious etiology for at least some CNS tumors.

General theories (not time period specific)

A few theories have been thought of:

  • High levels of Insulin-like growth factor-1 (IGF-1) [Renehan, 2004; Tower RL & Spector LG, 2007]
  • First-born effect [Schuz, 1999; Greaves, 2001; Shu, 2002; Jourdan-Da Silva, 2004]
  • Miscarriages [Yeazel, 1995]
  • Birth Defects [Savitz & Ananth, 1994; Nishi, 2000]
  • Cancer in the family [Hemminki & Mutanen, 2001]
  • Autoimmune disorders in the family [McKinney, 1987; Buckley, 1989; Perillat-Menegaux, 2003]

High levels of Insulin-like growth factor-1 (IGF-1)

IGF-1 is a polypeptide protein hormone similar in molecular structure to insulin (that's why it is called insulin-like). It plays an important role in childhood growth. IGF-1 has been shown to stimulate the growth of both myeloid and lymphoid cells in laboratory cultures. Hence, it has been proposed that high levels of IGF-1 may both produce a larger baby (higher birth weight) and contribute to leukaemogenesis. Studies investigated the birth weight (high and low) with leukaemia, neuroblastoma, Wilm's tumour, lymphoma, osteosarcoma and hepatoblastoma but mixed results have been reported.

First-born effect

Some observations on animals suggest that there may be an environmental cause for the first-born effect. Along the west coast of Florida, nearly all the firstborn bottlenose dolphin calves die before they separate from their mothers. This is thought to be due to the high levels of environmental toxins in the fat of marine mammals. Research suggests mother dolphins unload as much as 80 percent of their accumulation of pollutants into each of their calves, probably through nursing. By theory, the firstborn gets the highest dose of pollutant as the mother has been accumulating toxins for many years while subsequent siblings receive the toxins accumulated over shorter periods.
Some studies showed an increased risk of leukaemia, generally for those under 5 years of age, associated with being the firstborn. There are also negative results studies.


Maternal history of previous miscarriages is a frequently reported risk factor for development of childhood ALL in a subsequent child except for infant leukaemia.

Birth Defects

An increased incidence of birth defects has been reported in childhood cancer, particularly in leukaemia.

Cancer in the family

Studies showed parental cancer as a risk factor to childhood cancer for nervous system cancers (CNS), lymphomas, endocrine tumours and retinoblastoma but no excess risk for leukaemia and Wilm's tumour.

Autoimmune disorders in the family

The risk association have been reported between autoimmune disorders in the family and leukaemia (ALL) and lymphoma.