Exposure to a PAH before birth or via breast milk can lead to cancer.

Oct 23, 2008

Castro, DJ, C Lohr,  KA Fischer, CB Pereira and DE Williams. 2008. Lymphoma and lung cancer in offspring born to pregnant mice dosed with dibenzo[a,l]pyrene: The importance of in utero versus lactational exposure. Toxicology and Applied Pharmacology doi: 10.1016/j.taap.2008.09.009.




 
chemotherapy drips
Scientists have identified a critical time during late development in mice when a one-time exposure to a polycyclic aromatic hydrocarbon leads to a greatly increased risk of lymphoma and lung cancer later in life.
 
PAHs are released when cigarettes, coal and fossil fuels burn.
 
This study confirms there are vulnerable times during development and defines yet another disease that is preset by the womb environment surrounding a developing fetus.

Context

Childhood leukemia describes a family of diseases also known as blood cancers. There are at least four different types of leukemias and several different types of lymphomas. The type of leukemia or lymphoma is classified based on the type of blood cell that is causing the cancer.

In the United States, approximately 27% of all childhood cancers are leukemias. While leukemia survival has increased over the last 40 years, 22,000 people died from the disease in 2006 (National Cancer Institute 2006). Experts predicted an estimated 3,800 children (under the age of 20) would be diagnosed with leukemia in the United States in 2007, although exact figures are not yet available.

Treatment of new and recurrent cases of leukemia costs an estimated $2.6 billion dollars a year (Brown et al. 2002). This number does not include costs associated with job and/or productivity losses for patients and their families. If the total years of life lost to a malignancy are calculated, the societal impact of non-Hodgkin’s lymphoma (NHL; the fifth most common type of cancer), is greater than other cancers because of the disproportionate number of young people who die from the disease. Taking this life cost into account, NHL ranks as fourth among all malignancies in terms of economic impact in the U.S.

There is still a poor understanding of the underlying causes and risk factors associated with leukemia initiation and recurrence. Nevertheless, a growing body of evidence suggests that exposure to a variety of environmental factors particularly during the critical preconception and prenatal periods may be a contributing factor in increasing the risk for disease and disease recurrence (Birnbaum and Fenton 2003, Freedman et al. 2001, Meinert et al. 2000, Schüz et al. 2000; Shu et al. 1999, Stjernfeldt et al. 1986).

One class of environmental chemicals of growing concern in leukemia risk are polycyclic aromatic hydrocarbons (PAH). PAHs are found throughout the environment and are derived from incomplete burning processes. Sources include cigarette smoke, diesel exhaust and the industrial production of coke for making steel. Because PAHs are present in foods, a major route of exposure is via the diet (Luch 2005).

An estimated 11,000 metric tons of PAHs are released annually in the U.S. PAHs represent a “re-emerging” human health threat. Daily exposures from environmental sources are increasing, except for exposures from cigarette smoking, which has declined in the U.S. but remains prevalent in many other countries.

A major contributing factor to greater PAH exposure is the increasing need for energy - especially coal-based sources. An alarming expansion of the coal power industry is underway in China, now the largest consumer of coal in the world. Increased coal use in Asia affects U.S. citizens due to air currents carrying the contaminants across the Pacific Ocean. On any given day in the Los Angeles area, 25-33% of the atmospheric particulate matter (containing PAH) comes from China (Reisen and Arey 2005). The U.S. also obtains 50% of its energy from coal, and this percentage may increase as non-petroleum energy sources become increasingly important to the U.S. economy.
 

Dibenzo[a,l]pyrene (DBP) is the most potent PAH tested to date and is part of PAH mixtures found in the environment (Boström et al. 2002). DBP causes multi-organ cancer in many animals studied. It can cause lymphoma and cancers of the skin, endometrium, ovary, lung and liver (Boström et al. 2002, Buters et al. 2002, Higginbotham et al. 1993, Platt et al. 2004, Reddy et al. 1999a, Reddy et al. 1999b).

 

The authors' wanted to identify the critical time during development when  a common PAH called dibenzo[a,l]pyrene (DBP) causes lymphoma. This study follows earlier experiments that found mice exposed to DBP through their pregnant and nursing mothers developed highly aggressive lymphoma and lung cancer as adults. However, the scientists could not determine conclusively whether the detrimental PAH exposure occurred in the womb, while nursing or perhaps both.

The authors designed an elegant set of experiments where pregnant mice were given 15 mg/kg DBP during late pregnancy (day 17 of gestation) to replicate their earlier study. Once the baby mice were born, some were left with their birth mothers, and thus still possibly exposed to DBP through milk. A second group of mice were transferred to mouse foster mothers who had not been given DBP, so the pups would be nursing on DBP-free milk. A third set of mouse babies who had not been exposed to DBP in the womb, were fostered by mothers who had been exposed to DBP, so these pups would be drinking DBP-contaminated breast milk.

All of the pups, whether they were exposed to DBP prenatally, post-natally through lactation or both, were followed for 10 months and examined for signs of lymphoma (including distress, pain, death and tumors). 

Castro et al. found that late gestation was the most sensitive period for DBP exposure. Approximately 40% of the mice exposed to the chemical in the womb only died from complications associated with lymphoma and/or lung cancer. In comparison, more than 90% of the mice exposed to DBP only through their foster mother’s breast milk survived. Finally, in agreement with their earlier research, the authors found that DBP exposure both in the womb and while nursing was the most deadly, resulting in a 20% survival rate in the adult offspring 10 months later. 

As an independent study, Castro et al. stands on its own. The research finds that exposure to DBP during a critical window of development, notably late gestation, results in a significant increase in cancer risk in this rodent model. This is the first study to pinpoint the time frame when exposure is most likely to trigger blood cancers later in life.

However, when this study is considered in a broader context of leukemia/lymphoma risk, it strongly supports and adds more evidence to the idea that fetuses exposed to some environmental factors in the womb can develop long-term, adverse health problems. Indeed, this study is yet another piece of evidence in a complex puzzle that suggests many health problems and illnesses in children and adults - including testicular cancer, obesity, diabetes - can be traced back to exposures and altered genetic programming that occurred in the womb.

Some might argue this study has little human relevance because it was conducted in mice and at a relatively high dose of DBP. However, this line of reasoning ignores a growing body of peer-reviewed and published human data that have found associations between leukemia and lymphoma incidence in children and elevated chemical exposures in their mother’s during their pregnancies.

Specifically, Castro et al.'s finding is consistent with human research that has identified associations between exposure during pregnancy to growing number of household chemicals and childhood leukemias. This list includes, but is not limited to, paints, glues and solvents, cigarette smoke and pesticides (Birnbaum et al. 2003, Freedman et al. 2001, Meinert et al. 2000, Schuz et al. 2000, Shu et al. 1999, Stjernfeldt et al. 1986, Anderson et al. 2000, Rudant et al. 2007).

In addition to PAHs, the chemical exposure from using these products is broad and diverse. The Castro study indicates that PAH exposure, perhaps in a mixture with other harmful compounds, should be of concern, especially to pregnant mothers.

The critical time of exposure identified in this mouse study corresponds to the third trimester of pregnancy in people. Many cases of the life-threatening blood and lung cancers found in the older mice also develop in humans later in life during adolescence and young adulthood. Since air pollution - which is not bound to go away - is the major way pregnant women are exposed to PAHs, the researchers believe preventing exposure or finding ways through diet to counteract the DNA damage caused by chemical exposure during the critical development time is warranted.

Perhaps most importantly, Castro et al. confirms again that children, and particularly babies, with their growing and developing organs and tissues, are especially sensitive to chemicals in our environment. Exposure to these chemicals, especially in the womb can have long-lasting health consequences.

 

 Resources

Anderson, LM, BA Diwan, NT Fear and E Roman. 2000. Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models. Environmental Health Perspectives 108 Suppl 3:573-94.

Birnbaum, LS and SE Fenton. 2003. Cancer and developmental exposure to endocrine disruptors. Environmental Health Perspectives 111(4):389-94.

Boström, CE, P Gerde, A Hanberg, B Jernström, C Johansson, T Kyrklund, A Rannug, M Törnqvist, K Victorin and R Westerholm. 2002. Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air. Environmental Health Perspectives 110 Suppl 3:451-88.

Brown, ML, GF Riley, N Schussler and R Etzioni. 2002. Estimating health care costs related to cancer treatment from SEER-Medicare data. Medical Care 40(8 Suppl):IV104-17.

Buters, JT, et al. 2002. Cytochrome P450 1B1 determines susceptibility to dibenzo[a,l]pyrene-induced tumor formation. Chemical Research in Toxicology 15(9):1127-35.

 Freedman, DM, P Stewart, RA Kleinerman, S Wacholder, EE Hatch, RE Tarone, LL Robison and MS Linet. 2001. Household solvent exposures and childhood acute lymphoblastic leukemia. American Journal of Public Health 91(4):564-7.

Higginbotham, S, NVS. RamaKrishna, SL Johansson, EG Rogan and EL Cavalieri. 1993. Tumor-initiating activity and carcinogenicity of dibenzo[a,l]pyrene versus 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene at low doses in mouse skin. Carcinogenesis 14(5):875-8.

Luch, A. 2005. Polycyclic aromatic hydrocarbon-induced carcinogenesis – an introduction. The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons, ed. A. Luch. London: Imperial College Press, 1-18.

 Meinert, R, J Schüz, U Kaletsch, P Kaatsch and J Michaelis. 2000. Leukemia and non-Hodgkin's lymphoma in childhood and exposure to pesticides: results of a register-based case-control study in Germany. American Journal of Epidemiology 151(7): 639-46; 647-50.

National Cancer Institute. 2006. Surveillance Epidemiology and End Results. Cancer Stat Fact Sheets.

Platt, KL, HP Dienesb, M Tommasonea and A Luch. 2004. Tumor formation in the neonatal mouse bioassay indicates that the potent carcinogen dibenzo[def,p]chrysene (dibenzo[a,l]pyrene) is activated in vivo via its trans-11,12-dihydrodiol. Chemico-Biological Interactions 148(1-2):27-36.

Reddy, AP, U Harttig, MC Barth, WM Baird, M Schimerlik, JD Hendricks and GS Bailey 1999a. Inhibition of dibenzo[a,l]pyrene-induced multi-organ carcinogenesis by dietary chlorophyllin in rainbow trout. Carcinogenesis 20(10):1919-26.

Reddy, AP, et al. 1999b. Experimental hepatic tumorigenicity by environmental hydrocarbon dibenzo[a,l]pyrene. Journal of Environmental Pathology, Toxicology and Oncology. 18(4):261-9.

Reisen, F and J Arey. 2005. Atmospheric reactions influence seasonal PAH and nitro-PAH concentrations in the Los Angeles basin. Environmental Science and Technology 39(1):64-73 .

Rudant, J, F Menegaux, G Leverger, A Baruchel, B Nelken, Y Bertrand, C Patte, H Pacquement, C Vérité, A Robert, G Michel, G Margueritte, V Gandemer, D Hémon and J Clavel. 2007. Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE). Environmental Health Perspectives. 115(12):1787-93.

 Schüz, J, U Kaletsch, R Meinert, P Kaatsch and Jörg Michaelis 2000. Risk of childhood leukemia and parental self-reported occupational exposure to chemicals, dusts and fumes: results from pooled analyses of German population-based case-control studies. Cancer Epidemiology Biomarkers and Prevention 9(8):835-8.

 Shu, XO, P Stewart, W-Q Wen, D Han, JD Potter, JD Buckley, E Heineman and LL Robison. 1999. Parental occupational exposure to hydrocarbons and risk of acute lymphocytic leukemia in offspring. Cancer Epidemiology Biomarkers and Prevention 8(9):783-91.

 Stjernfeldt, M., J Ludvigsson, K Berglund and J Lindsten. 1986. Maternal smoking during pregnancy and the risk of childhood cancer. Lancet 2(8508):687-8.

Lymphoma and synthetic chemicals

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