Prevalence of K-ras mutations at diagnosis and serum levels of DDT, DDE, PCBs and other organochlorine compounds in exocrine pancreatic cancer

The possibility that organochlorine compounds play a role in the pathogenesis of exocrine pancreatic cancer through modulation of K-ras effects could have significant implications for research on the carcinogenic process of this and other malignancies associated with K-ras mutations. Future studies should be based on mechanistic scenarios that integrate evidence from molecular biology, molecular pathology, molecular epidemiology, genetic toxicology, clinical medicine, and environmental chemistry. Whereas organochlorine compounds are ubiquitous throughout the planet and have a wide range of physiologic effects, no clinical or public health inferences are warranted until our findings are replicated in new studies.

1. Introduction

Agents such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,p'-DDT), its main metabolite and environmental degradation product, 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE), several polychlorinated biphenyls (PCBs), hexachlorobenzene and hexachlorocyclohexane comprise the bulk of organochlorine residues in human tissues. These compounds are ubiquitous throughout the planet, poorly excreted due to their lipophilic properties, and stored in many human tissues [2-9]. DDT was widely used in the past as a pesticide, and it continues to be used, mainly for controlling malaria; total global use (worldwide) may be as great at present as it was in the 1970s [2]. PCBs have been used in insulating and cooling electrical equipment (transformers, capacitators, fluorescent lamps), paints, inks, carbonless copy paper, adhesives, resins, plasticisers and many other products and processes [5-9].

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2. Subjects and Methods

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3. Results and Discussion

In studies on organochlorine compounds it is common to find patients whose concentration of a given compound falls below the limit of detection or lies between such limit and the limit of quantitation. However, there is no general agreement among epidemiologists as to how statistical analyses should deal with these values. Figure 1a shows the distribution of values for DDT analogues. Levels of p,p'-DDT were detectable in 36 of the 51 cases (71%); in 6 cases (12%) they were detectable but not quantifiable. All 51 cases of EPC had detectable concentrations of p,p'-DDE, and these were quantifiable in 92% of subjects. Ten PCB congeners were detected; for 7 of them (IUPAC numbers 28, 52, 101, 118, 170, 187 and 194) over half of cases had non-detectable or non-quantifiable levels (figure 2a), and they were thus no longer considered. By contrast, all 51 cases of EPC had detectable levels of congeners 153 and 180, and 43 cases (84%) of PCB 138. The corresponding distribution for the rest of organochlorine compounds is shown in figure 3a. Hexachlorobenzene and b-hexachlorocyclohexane were detected in all cases.

In our study, limits of detection and quantitation were 0.1 and 0.3 ng/mL, respectively (detailed figures for all compounds are available from the authors). When organochlorine serum concentrations were not detected we assigned a value of zero. When a compound was detected but the concentration was under the quantitation threshold, the mid-value between detection and quantitation limits was assigned. The resulting values are shown in table 3, as well as in figures 1b, 2b and 3b (the horizontal line of the box plot represents the median value).

The Total PCBs value was the arithmetic sum of the concentrations of all PCB congeners after value imputation (as described in the previous paragraph). Exposure to PCBs was analysed with a congener-specific approach (i.e., each congener separately), as recommended [8,9]. The variable Total PCBs was used only in multivariate analyses to further adjust DDT and DDE levels (i.e., to separate the effects of DDT and DDE from the effects of PCBs). There were two reasons to do so. First, as mentioned, levels of 7 congeners were often undetected or unquantifiable in the patients (figure 2a, table 3), and the resulting Total PCBs was a construct substantially based on imputed values. Second, Total PCBs mixes congeners with different persistence, hormonal activities, cytochrome P450 inducibility, and carcinogen-promoting potential [1,5-9]. For descriptive purposes, and to enable comparison with other studies, table 3 presents several statistics, both on a wet basis (nanograms per milliliter, which is equivalent to parts per billion [ppb]), and on a lipid basis (expressed as micrograms of the organochlorine compound per gram of Total Lipids). The compound present at highest concentrations was p,p'-DDE, followed by b-hexachlorocyclohexane and hexachlorobenzene (table 3, figures 1b and 3b).

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Table 1.

Personal and lifestyle characteristics of exocrine pancreatic cancer cases sampled and not sampled for serum organochlorine analyses

Table 2.

Symptom history and characteristics at presentation of exocrine pancreatic cancer cases sampled and not sampled for organochlorine analyses

Figure 1a

Figure_1b

Figure_2a

Figure_2b

Figure_3a

Figure_3b

Table 3.

PANKRAS II Study: Organochlorine concentrations among cases of exocrine pancreatic cancer (n = 51)

Table 4.

Case-control comparison. Serum concentration among all 51 cases of exocrine pancreatic cancer are compared to concentrations among the 26 hospital controls

Table 5.

Serum concentrations (median, ng/mL) of p,p'-DDT, p,p'-DDE and the three predominant PCBs among controls, and among cases of exocrine pancreatic cancer with and without mutations in the K-ras gene

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Acknowledgements

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References