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Two phenomena, one of which relates to the area of human reproduction and the other to the frequency, distribution, and control of disease in a population have emerged in the previous century and continue intensively to develop nowadays. Both these phenomena are directly related to the changes which are occurring in the incidence and prevalence of malignant tumours, as well as to mortality from them and to the opportunities for cancer control. The first of these phenomena has been denominated as the demographic, and the second as the epidemiological transition. The commonly accepted definition of the demographic transition is currently applied to designate a sustainable change in the type of population reproduction, when an initial and abrupt acceleration of population growth is replaced by its rapid deceleration with a subsequent stabilization of a population and a sharp change in its age structure. Demographic transition develops in a brief historical space of time and has the character of a global process. Population ageing and disequilibrium between the younger and older generations are the most important consequences of the demographic transition, and must inevitably influence the strategy and implementation of national cancer control programs. As life expectancy increases, so does the certainty that people will become more and more prone to diseases that are more common among older age groups, i.e. noncommunicable diseases and cancer in particular, rather than being affected by epidemics of infectious diseases. This situation is known as the epidemiological transition and reflects spectacular shifts in the pattern and causes of death and morbidity that have taken place in the vast majority of countries over the previous century. Epidemiological transition results in accession by poor countries to the problems of the rich, and leads to the "double burden" of disease in countries whose economies are undergoing transition, because of the still continuing burden of endemic infectious diseases. Russia is entering the final stages both of the demographic and the epidemiological transition, a period when numerous reasons, increasing demands on the systems of social protection and public health are inevitable. During the years 1992 to 2001, cancer incidence increased from 271.8 up to 313.9 per 100,000 population, i.e. a growth of over 16% and an annual rate of growth of 1.7%. According to the global estimates provided by the International Agency for Research on Cancer the number of new cancer cases in the year 2000 exceeded 10 million, and the number of deaths from cancer reached 6.2 million. The annual growth rate of global cancer incidence during the last 25-30 years was higher than the global population growth rate. Analysis of data available from population based cancer registries in Russia and abroad confirms the conclusion that cancer is mainly the fate of people belonging to the older age groups. Given the levels of exposure to specific carcinogens and genetic predisposition factors, the incidence of cancer should be considered as an exponential function of age. The unfeasibility of attempts to change, in the foreseeable future, the rate and trend of demographic transition and demographic ageing, in particular, is obvious. It would therefore be more feasible to envisage their probable consequences and to adapt the limited resources of national health and social support services to the needs of cancer control, which will significantly increase in the near future.

The modifying effect of pregnancy and lactation on carcinogenesis induced by single injection of 1,2-dimethylhydrazine to female rats 30 days before mating has been studied. The total incidence of malignant tumours in rats with pseudopregnancy, single pregnancy, pregnancy and lactation, repeated pregnancies was lower in comparison with virgin animals (75, 44, 68, 59 and 93%, respectively). Colon adenocarcinoma incidence in rats with single pregnancy or repeated pregnancies was lower than that in virgin rats (42, 49 and 76%, respectively). Protective effect was observed mainly in descending colon. The mesenchymal kidney tumours were not developed at all in rats with single pregnancy. In virgin animals it was 31%. The inhibition of tumour incidence in the liver (cholangioma, cholangiocellular carcinoma) was observed in rats with single pregnancy or pregnancy and lactation in comparison with virgin control (3, 5 and 24%, respectively).

Pregnant SHR mice were treated once with 7,12-dimethylbenz[ a ]anthracene (DMBA) on days 17 – 19 of gestation. F1 and F2 descendants of these mice received multiple skin applications of 12- O -tetradecanoylphorbol-13-acetate (TPA) twice a week for 24 weeks beginning at 12 weeks of age, or applications of solvent alone. The increase in the frequency of skin tumours in F1 and F2 descendants was reported elsewhere. In addition, we report here an increase in overall numbers of tumor-bearing animals, independently of TPA treatment both in F1 and F2 groups compared to respective control groups. Separate statistical analyses were performed for lung tumours, mammary gland tumours, leukaemias and lymphomas. In both generations of descendants of DMBA-treated mothers lung tumour incidence was considerably increased and differed significantly (maximal P -value = 0.003) from control values. Local applications of TPA resulting in strong skin tumour promoting effect described in our previous paper (Napalkov et al., Carcinogenesis, 8(3) (1987) 381) did not produce any significant change in the rates of other types of tumours. The results of the present study provide additional evidence in support of the hypothesis on possibility of hereditary transmission of carcinogenic action of certain chemical compounds.

Thyroid dysfunction (induced by thyroidectomy or administration of thyroxin and methylthiouracil) during the postnatal period was tested as a modifying factor on carcinogenesis induced transplacentally by N-methyl-N-nitrosourea (MNU). It resulted mainly in inhibition of tumours of the nervous system and kidney in rats of two subsequent generations, but thyroid carcinogenesis was increased. Postnatal disturbance of oestrous function (induction of persistent oestrus syndrome) in female rats increased the incidence of tumours of the central nervous system induced transplacentally by MNU or 7,12-dimethylbenz[a]anthracene. No such effect was seen in animals of the F2 generation.

Transplacental carcinogenic effects have been demonstrated for about 60 chemicals in eight animal species and even in the human. Many carcinogens are much more active in the fetus than in the adult animal. The stage specificity of transplacental carcinogenesis is characterized by the possibility of inducing tumors only at certain stages of embryogenesis (at the end of organogenesis and during the whole period of histogenesis). Risk of transplacental carcinogenesis is owing to the passage of carcinogens or their active metabolites into embryonic tissue and the possibility of metabolic activation of substances within the fetus. In this connection, four main pathways can be hypothesized for the carcinogenic effect of a substance on the fetus. Organotropism with transplacental carcinogenesis is determined by genetic predisposition, differentiation, and proliferative activity in the target tissues. For indirect carcinogens the level of metabolizing enzymes is also important. Teratogenesis and carcinogenesis can be either independent processes or pathogenetically related to each other (eg, DES action). Experimental data can readily be applied to the discussion of prophylaxis of prenatal tumors in the human.

During the late period of pregnancy (on the 50th and 53rd days post coitum) 2 dogs were injected intraperitoneally with 100 mg/kg (a single administration) of nitrosoethylurea. Nine puppies were born. During the 9 year period of observation no tumours were detected in mother-dogs. Three of 9 offspring developed the following tumours: brain haemangioblastoma (on the 526th day after administration), nephroblastoma and spleen angioleiomyoma (on the 845th day after administration) and adenoma of thyroid gland (after 7 years). Among other lesions 3 offspring-dogs developed polycystic kidneys. The revealed tumours of brain, kidney and spleen could be connected with transplacental carcinogenic effect of N -nitro-soethylurea (NEU), while neoplasms of these localizations and types rarely occur in dogs spontaneously.

N-nitrosoethylurea (NEU) is found to show an intensive transplacental carcinogenic effect inducing in mice different neoplasms, mainly lung adenomas. Postnatal x-ray irradiation of control animals resulted in the occurrence of ovarian tumors in some female mice. Delivary and feeding of the progeny would lead to the development of mammary gland tumors in a number of control female animals. Postnatal exposure to x-rays of mice exposed to transplacental effect of NEU resulted in the increased incidence of lung neoplasms, mainly adenocarcinomas.

Outbred mice on the 19th-21st day of pregnancy were injected intravenously 3,4-benzpyrene (BP) in the dosage of 15 mg/kg or 9,10-dimethyl-1,2-benzanthracene (DMBA) in the dosage of 40 mg/Kg in control groups, and moreover preliminary injected BP (24 hours before) in experimental groups. The BP concentration of embryos and the maternal liver 15 minutes following the injection of the basic dose of the carcinogen in increased dosage of preliminary exposure first would decrease, reach the minimum, in preliminary dosage equal to 0.75 mg/Kg, and then would increase up to values observed in control experiments with the dosage of 30 mg/Kr 7.5-15 mg/Kg, and then it would fall again in the dosage of 30 mg/Kg. The preliminary injection of BP in the dosage of 0.75 mg/Kg produced a sharp fall in the carcinogen concentration in embryos and the maternal organism during the first moment of observation (after 5 minutes), but it failed to influence the rate of subsequent decrease of the substance level. An explanation of the two effects observed is suggested based on the assumption that there exist two enzymatic systems metabolizing BP: one-premanently present in the liver and the other-induced by the carcinogen. The preliminary BP injection did not influence the concentration of DMBA.

In the experiments with transplacental exposure of mice to N-nitrosoethyl urea (NEU) an enhanced carcinogenesis was noted not only in the first but also in the second generation. This effect in mice of the second generation was manifested in earlier development, as compared with control animals, of different neoplasms as well as in somewhat increased frequency of their detection. Postnatal exposure to NEU would enhance carcinogenesis in mice of both experimental and control groups, whereas no enhancement of carcinogenesis was observed in animals exposed to NEU in progenesis, compared with control mice. Postnatal x-ray irradiation also failed to produce enhanced carcinogenesis, compared with control animals i.e. those exposed to NEU in progenesis. While in female mice of the same group, contrary to the control, ovarian tumors under the effect of irradiation did not arise. It is suggested that there is a pathogenic connection between the inheritance of carcinogenic effect by oocytes and the loss by the ovary its capacity to produce neoplasms in response to irradiation.

The authors have studied the time course of changes in N-nitrosodimethylamine (NDMA) concentration in the blood, liver, muscle tissue and embryo of pregnant rats and mice after its intravenous injection in a dose of 50 mg/kg. In the parent organism, the maximal concentration was attained immediately after injection as shown by the measurements made 5 minutes after and then decreased according to the exponential law, with that decrease occurring far rapidly in mice than in rats. In the embryo, the maximal concentration attainment was 30-60 minutes as delayed. The concentration of NDMA in the embryo and tissues of the parent organism ascended linearly up to a definite level as the dose was raised (blood concentration) whereupon its increase became slower and even ceased which forms the basis for an assumption that the carcinogenic substance penetrates via the placenta and cell membranes according to the laws of transport with the aid of carriers.

The paper discusses the influence of deranged function of the thyroid (in postnatal period) on the transplacental carcinogenic effect of N-nitrosomethylurea (NMU) in albino noninbred rats. It was found that exogenous thyroxin-induced hyperthyroidism and thyroid function suppression either by long-term treatment with a thyreostatic agent--methylthiouracil (MTU) or thyroidectomy are followed by a lower frequency of, chiefly, nervous system tumors which are typical of NMU-induced transplacental carcinogenesis in rats. Moreover, transplacental treatment with NMU potentiated the carcinogenic effect of MTU on the thyroid. The latter manifested itself in a higher frequency of malignancies of the thyroid in animals exposed to a combined treatment with NMU (transplacentally) and MTU (postnatally) as compared with those given MTU only (postnatally).

Pregnant SHR mice were treated once with 7,12-dimethylbenz[a]anthracene (DMBA) on day 17-19 of gestation, and F1 and F2 descendants received multiple skin applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) twice a week for 24 weeks beginning at 12 weeks of age. Post-natal promoter treatment resulted in a high incidence of skin tumours in F1 and F2 mice (37.3 and 19.7%, respectively), whereas only 6.6% of control animals treated with TPA only developed skin tumours. DMBA was shown previously to be capable of initiating skin carcinogenesis transplacentally; however, our results on the second generation provide suggestive evidence of hereditary transmission of at least part of the initiating action of this carcinogen.

We showed earlier that 5-bromodeoxyuridine (BrdUrd), which can substitute for thymidine during DNA synthesis, inducing transition mutations, is incorporated into DNA of various tissues when administered to newborn rats and is not subjected to repair processes. The main purpose of the present experiment is to verify if a direct perturbation of DNA would be sufficient to initiate carcinogenesis. Rats aged 1, 3, 7, and 21 days were given BrdUrd s.c. at a dose of 3.2 mg/animal. At 2 months some of the females were subjected to treatment known to induce persistent estrus; at 1 month a group of males underwent removal of one kidney, and groups of males and females were exposed to a single total-body X-irradiation at a dose of 1.5 Gy (150 rads) per rat. In females, treatment with BrdUrd induced tumors of the ovaries, polyps in the uterus, and tumors of the soft tissues, nervous system, forestomach, glandular stomach, and salivary gland; no such tumor occurred in control females. Induction of persistent estrus increased the incidences of ovarian tumors and of malignant tumors of the uterus. Treatment with BrdUrd also increased the carcinogenic effect of X-rays on the mammary gland. In males, BrdUrd induced tumors of the testis (seminomas) and adenomas of the thyroid gland; solitary tumors of the kidney, nervous system, soft tissues, and bladder were also found. Unilateral nephrectomy reduced the incidences of tumors in the testis and pituitary gland, whereas subsequent treatment with X-rays did not alter the incidences of tumors induced by BrdUrd. These studies demonstrated for the first time that a nucleoside analogue, BrdUrd, has carcinogenic potential. Possible molecular mechanisms for its carcinogenicity and for the effects of the promoting factors are discussed.

The F1 rats subjected to the influence of N-nitrosomethylurea (NMU) in dose of 20 mg/kg on the 21 day gestation as a result of postnatal disturbances of the thyroid function induced by long administration of thyroxin (3 mg/100 g, daily), methylthiouracil (MTU; 0.1% solution in tap water) or thyroidectomy have shown a decreased incidence of the nervous system tumours, but not of the kidney tumours, i. e. sites typical of NMU transplacental carcinogenesis. At the same time the NMU transplacental effect increased thyroid carcinogenesis, induced by the MTU postnatal application, which manifested in the increased incidence of malignant tumours of this site. The carcinogenic effect was observed in F2 rats, while some of them developed tumours of the nervous system (14.9%) and kidney (8.5%) but with lower incidence than in F1 (35.4; 14.1%, respectively). The same modifying factors (thyroxin, thyroidectomy, MTU) employed under the same conditions produca similar effect on carcinogenesis in F2 animals.

Formation and loss of methylated purines in DNA of various fetal and maternal tissues were measured up to 7 days following intravenous administration of N-[14C]methyl-N-nitrosourea to rats on the 21st day of gestation. Methylation products were detected in all tissues examined, the level in maternal liver being higher than in other tissues. The concentrations of 7-methylguanine and 3-methyladenine decreased faster in fetal than in corresponding maternal tissues, due to a higher rate of DNA synthesis in fetal tissues, as determined by incorporation of labelled thymidine. Removal of the promutagenic DNA lesion O6-methylguanine was most efficient in maternal and fetal liver; but it was very poorly repaired in kidney and brain. The persistence of O6-methylguanine relative to 7-methylguanine was highest in the DNA of fetal brain. The principal targets for the transplacental carcinogenic effect of N-methyl-N-nitrosourea under these experimental conditions were fetal neurogenic tissue and kidney; and malignant tumors developed at these sites in 31-34% and 15-16% of male and female descendants, respectively. These results support the concept that a complex interaction between DNA alkylation, repair and replication is the molecular basis of initiation of carcinogenesis by alkylating agents.