Evidence for repetitive load in the trapezius muscle during a tapping task.

Many studies describe the trapezius muscle activation pattern during repetitive key-tapping focusing on continuous activation. The objectives of this study were to determine whether the upper trapezius is phasically active during supported key tapping, whether this activity is cross-correlated with forearm muscle activity, and whether trapezius activity depends on key characteristic. Thirteen subjects (29.7 ± 11.4 years) were tested. Surface EMG of the finger's extensor and flexor and of the trapezius muscles, as well as the key on-off signal was recorded while the subject performed a 2-min session of key tapping at 4 Hz. The linear envelopes obtained were cut into single tapping cycles extending from one onset to the next onset signal and subsequently time-normalized. Effect size between mean range and maximal standard deviation was calculated to determine as to whether a burst of trapezius muscle activation was present. Cross-correlation was used to determine the time-lag of the activity bursts between forearm and trapezius muscles. For each person the mean and standard deviation of the cross-correlations coefficient between forearm muscles and trapezius were determined. Results showed a burst of activation in the trapezius muscle during most of the tapping cycles. The calculated effect size was ≥0.5 in 67% of the cases. Cross-correlation factors between forearm and trapezius muscle activity were between 0.75 and 0.98 for both extensor and flexor muscles. The cross-correlated phasic trapezius activity did not depend on key characteristics. Trapezius muscle was dynamically active during key tapping; its activity was clearly correlated with forearm muscles' activity.

[Conservative surgery for kidney cancer: Indications and results based on a review of 40 patients]. / Chirurgie conservatrice du rein pour cancer : indications et résultats. A propos d'une revue de 40 patients.

OBJECTIVES: To evaluate the oncological and functional results in patients treated by conservative surgery for kidney cancer and to study the intraoperative and postoperative morbidity. MATERIAL AND METHODS: Retrospective, single-centre study based on 40 consecutive patients undergoing a conservative surgery for kidney cancer between March 1997 and July 2006. Patients had a mean age of 60 years (range: 26-81 years) and the surgical indication was elective in 75% of cases (n=30) and mandatory in 25% of cases (n=10). Preoperative mean creatinine and creatinine clearance were 101mol/l (53-237mol/l) and 80ml/min (35-147ml/min), respectively. Tumours were classified according to the TNM 2002 classification as stage T1a (75%), T1b (20%) and T2 (5%). Guided kidney aspiration biopsy was performed in 80% of patients. The main endpoints were positive surgical margins, local recurrence, intraoperative complications and postoperative renal function. Secondary endpoints were postoperative complications, need for blood transfusion, surgical revision, operating time and hospital stay, metastatic disease and overall and specific survival. Statistical analysis was performed with SPSS 13.0.1 software. RESULTS: With a mean follow-up of 44 months (range: 15-134 months), one patient (2.5%) presented local recurrence. The positive surgical margin rate was 5% and overall and specific survivals were 97.5%. No metastases have been observed. Serum creatinine was increased and creatinine clearance was significantly decreased (P<0.05) after the operation, with no clinical consequences. The urinary fistula rate was 5%, blood transfusion and surgical revision were required in 5% of cases respectively, the mean operating time was 128minutes and the mean hospital stay was 8.1 days. CONCLUSION: Mandatory, relative or elective conservative kidney surgery gives functional and oncological results at least equivalent to those of radical nephrectomy, with the advantage of nephron-sparing surgery. It should be suggested as first-line procedure whenever possible, even when the contralateral kidney is healthy.

[Value of percutaneous kidney biopsy in the management of solid renal tumours less or equal to 4 cm]. / Intérêts des ponctions biopsies rénales percutanées dans la prise en charge des tumeurs solides du rein inférieures ou égales à 4 cm.

OBJECTIVE: To assess the value of diagnostic percutaneous kidney biopsy of solid renal tumours less or equal to 4 cm and its impact on management. MATERIALS AND METHOD: From January 2001 to October 2006, all solid renal tumours less or equal to 4 cm were systematically assessed by CT-guided percutaneous biopsy: 66 tumours were biopsied in 65 patients (one bilateral tumour) and four patients had a second biopsy. A total of 70 biopsies were performed. RESULTS: Among the biopsies, 18% (12/66) were not contributive. Four were repeated and provided a diagnosis in 50% of cases. Two patients with non contributive biopsies were lost to follow-up. Seven benign tumours (10.9%) and 54 malignant tumours were diagnosed. The kidney biopsy diagnosed 91% (52/57) of malignant tumours and 57% (4/7) of benign tumours. The concordance between biopsy results and pathology results was 90.7% for histological type of tumour and 64% for Fuhrman nuclear grade. Histological type and tumour grade had no impact on the type of surgery performed (51 patients operated, 29 kidney-preserving procedures, by necessity in seven cases). Four patients (6.3%) in whom a benign tumour was diagnosed on biopsy were simply followed, thereby avoiding surgery. CONCLUSION: This series revealed 10.9% of benign tumours, only 57% of which were diagnosed by biopsy. Management was modified for only four patients (6.3%). Kidney biopsy remains an option in the pretreatment assessment of renal tumours less or equal to 4 cm, but cannot be proposed systematically.

Modulation of leg muscle activity and gait kinematics by walking speed and bodyweight unloading.

During rehabilitation, many patient groups are being trained using bodyweight-supported treadmill training. However, little is known about modulation of time and distance parameters, joint movements and leg muscle EMG patterns by very low walking speeds or partial bodyweight unloading. We collected data from 20 healthy young volunteers who walked on a treadmill at walking speeds varying between 0.5 and 5.0 km h(-1) (0.14-1.39 ms(-1)) and with 0%, 25%, 50% and 75% bodyweight unloading. We found that cadence and stride length were largely influenced by walking speed, while bodyweight unloading influenced these measures only at 75%. However, the relative duration of the gait phases changed largely only at walking speeds less than 2.5 km h(-1), but was influenced by all different bodyweight unloading conditions. Joint trajectories of knee and ankle joint, as well as leg muscle EMG activity patterns changed largely at walking speeds slower than 2.5 km h(-1) and with 75% bodyweight unloading. We concluded that the parameters we investigated changed minimally at walking speeds faster than 2.5 km h(-1) and bodyweight unloading conditions less than 50%. Therefore, standards for EMG activity and joint angle trajectories should only be compared when the training is done with velocities higher than 2.5 km h(-1) and less than 50% body weight unloading.

Mutagenicity of extracts of pickled vegetables collected in Linhsien County, a high-incidence area for esophageal cancer in Northern China.

Extracts of pickled vegetables commonly consumed in Linhsien County, a high-incidence area for esophageal cancer in Northern China, were studied for mutagenicity. The liquid residue from ethereal extracts produced a dose-dependent increase of mutants in Salmonella typhimurium TA98 and TA100 strains; mutagenicity required the presence of a fortified liver microsomal activation system induced by Aroclor 1254 in adult male BD VI inbred rats. An amount of extract equivalent to 2.8 g fresh pickled vegetables produced sixfold (75 revertants/g) and twofold (45 revertants/g) increases in revertant frequencies in strains TA98 and TA100, respectively. Roussin's red methyl ester, a tetranitroso compound, [(NO)2Fe(CH3S)]2, not previously reported to occur in nature, was isolated and identified from the ethereal extracts. The synthetic compound was mutagenic in strain TA100 in the presence of a liver activation system, producing 25 revertants/mumol. Findings on the presence of mutagenic compounds in pickled vegetables were discussed in relation to their possible etiologic role in cancer of the esophagus in Linhsien County.

Legislation concerning chemical carcinogens in several industrialized countries.

A survey was carried out on legislation in 14 industrialized countries relating to the prevention of occupational cancers. Two types of legislation were considered in particular: that dealing specifically with chemical carcinogens in the working environment, and that relating to compensation for occupational cancers. The survey revealed that legislation prohibiting the manufacture of chemicals known to be carcinogenic in humans or known to represent a possible cancer hazard to humans exists only in a limited number of the 14 countries considered and does not cover the same chemicals in each country. Legislation concerning monetary compensation is more common in these countreis than is legislation providing for primary prevention. There are two fundamental deficiencies in even the more comprehensive legislation. First, some chemicals for which carcinogenicity in humans has been proved are still produced in large quantities and are not covered by legislation. Second, the criteria used to determine which chemicals may be hazardous to humans when only experimental evidence of carcinogenicity exists are overexclusive, while the allowed concentrations of some of the chemicals recognized as possibly hazardous to humans appear to be very high.

An evaluation of chemicals and industrial processes associated with cancer in humans based on human and animal data: IARC Monographs Volumes 1 to 20.

An international ad hoc Working Group of experts in cancer research met at the International Agency for Research on Cancer (IARC) in January 1979 to evaluate the data on human and experimental animal carcinogenicity for 54 chemicals, groups of chemicals, and industrial processes. Monographs for these chemicals were published in Vols. 1 to 20 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Based on evidence from human studies, 18 of the 54 chemicals or industrial processes are human carcinogens. A further 18 chemicals are probably carcinogenic for humans, although the data were considered not adequate to establish a causal association. To reflect differing degrees of evidence of carcinogenicity within this group, the chemicals were further subdivided, with 6 chemicals exhibiting a high degree of evidence and 12 chemicals exhibiting a lower degree. Data on the remaining 18 chemicals were considered insufficient to allow any evaluation of carcinogenicity. The report summarizes the background, purpose, and overall conclusions of the Working Group. The evidence supporting the evaluations is given in the "Appendix."

5-Bromodeoxyuridine-induced carcinogenesis and its modification by persistent estrus syndrome, unilateral nephrectomy, and X-irradiation in rats.

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.

Carcinogenicity of chloroethylene oxide, an ultimate reactive metabolite of vinyl chloride, and bis(chloromethyl)ether after subcutaneous administration and in initiation-promotion experiments in mice.

Repeated s.c. administration of chloroethylene oxide, a reactive metabolite of the carcinogen vinyl chloride, induced local tumors in mice, with an incidence comparable to that of bis(chloromethyl)ether, a structurally related human and animal carcinogen, when both compounds were applied at maximum tolerated chronically toxic doses; no tumors distant from the injection site were produced. Bis(chloromethyl)ether, chloroethylene oxide, and its rearrangement product chloroacetaldehyde, a highly toxic compound, were further tested in an initiation-promotion experiment. Application to the skin of a single dose of either bis(chloromethyl)ether or chloroethylene oxide, followed by 3-times-weekly applications of 12-O-n-tetradecanoylphorbol-13-acetate for 42 weeks, produced skin tumors in mice; chloroacetaldehyde under comparable conditions produced no increase in benign or malignant tumors. A good correlation between the chemical reactivity, on the basis of hydrolysis constants in aqueous media, and the carcinogenicity of the three compounds was noted. Our results support the hypothesis that epoxidation of the thylenic double bond in vinyl chloride yields an ultimate carcinogenic metabolite, chloroethylene oxide, a highly reactive compound which appears also to be largely responsible for the known genetic changes caused by the parent compound.

Evaluation of the carcinogenicity of chemicals: a review of the Monograph Program of the International Agency for Research on Cancer (1971 to 1977).

In 1971 the International Agency for Research on Cancer initiated a program on the evaluation of the carcinogenic risk of chemicals to humans, which concentrated on the production of monographs on individual chemicals. A review of this ongoing program is presented here as a contribution to the discussion of primary prevention of cancer. A total of 368 chemicals were evaluated in the first 16 volumes of the International Agency for Research on Cancer monographs. For 26 chemicals (or industrial processes), a positive association between exposure and the occurrence of cancer in humans was observed. For 221 chemicals, some evidence of carcinogenicity was found in at least one species of experimental animals. However, no evaluation of the carcinogenic risk of these chemicals to humans was made, either because no epidemiological studies or case reports were available or because the results of available human studies were inconclusive. For the remaining 121 chemicals, the available data were inadequate for an evaluation of the presence or absence of a carcinogenic effect in experimental animals or humans. The criteria on which the carcinogenicity of chemicals to humans and/or experimental animals was assessed, from the initiation of this program in 1971 until 1977, have recently been revised and are briefly discussed.

Contribution of aflatoxin B1 and hepatitis B virus infection in the induction of liver tumors in ducks.

The study of two major risk factors in the development of hepatocellular carcinoma, namely persistent hepatitis virus infection and exposure to dietary aflatoxins, has been hampered by lack of an experimental system. To this end we have used a Pekin duck model to examine the effect of congenital duck hepatitis B virus (DHBV) infection and aflatoxin B1 (AFB1) exposure in the induction and development of liver cancer. AFB1 was administered to DHBV infected or noninfected ducks at two doses (0.08 and 0.02 mg/kg) by i.p. injection once a week from the third month posthatch until they were sacrificed (2.3 years later). Two control groups of ducks not treated with AFB1 (one of which was infected with DHBV) were observed for the same period. Each experimental group included 13-16 ducks. Higher mortality was observed in ducks infected with DHBV and treated with AFB1 compared to noninfected ducks treated with AFB1 and other control ducks. In the groups of noninfected ducks treated with high and low doses of AFB1, liver tumors developed in 3 of 10 and 2 of 10 ducks; in infected ducks treated with the high dose 3 of 6 liver tumors were observed and none in the low dose of AFB1. No liver tumors were observed in the two control groups. Ducks infected with DHBV and treated with AFB1 showed more pronounced periportal inflammatory changes, fibrosis, and focal necrosis compared to other groups. All DHBV carrier ducks showed persistent viremia throughout the observation period. An increase of viral DNA titers in livers and sera of AFB1 treated animals compared to infected controls was frequently observed. No DHBV DNA integration into the host genome was observed, although in one hepatocellular carcinoma from an AFB1 treated duck, an accumulation of viral multimer DNA forms was detected. The metabolism of AFB1 in infected and noninfected duck liver was also examined. The study on the role of DHBV infection and AFB1 in the etiopathogenesis of liver tumors may help to clarify some of the basic mechanisms of carcinogenesis.

Between the body and the mind: the involvement of psychological factors in the development of multifactorial diseases.

A possible aetiological role for psychological factors has been propounded in particular in relation to diseases of which the causes are only partially known and which are in most cases multifactorial, such as cancer. The long period between a possible first event and the point of no return, gives appeal to the belief that life events other than "material" causes may play a role in cancer. The evidence that the immune and the nervous system may produce the same substances has opened the way to a new area of research. However, a lack of standardised instruments and the difficulty of conducting systematic and adequate analyses of potential confounding variables have discouraged most qualified scientists from devoting time and effort to investigating the possible role of psychological factors in the aetiology of human diseases. A few studies have reported a positive association between severe life events and breast cancer, but the prevailing view of the medical establishment is that there is no true association between stress and the onset of breast cancer. Although many criticisms of the studies reporting a positive association are definitely based on solid arguments, at least some of the criticisms cling to the requirement for absolute certainty in establishing a cause-effect relationship, which epidemiological studies can rarely, if ever, provide. A challenge for the future of research will be to investigate and better understand the role of subjective factors on the course and outcome of various pathologies, and in modulating the risk of developing a pathology.

Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals.

Diethylstilboestrol (DES) exerts several toxic effects in experimental animals, by mechanisms which are still unclear. The genotoxicity of the drug has been attributed to a quinone metabolite and is mainly clastogenic, including sister chromatid exchange, unscheduled DNA synthesis, chromosomal aberrations, disruption of mitotic spindle and aneuploidy. There is evidence that genotoxic effects may occur also transplacentally. Intrauterine and early postnatal exposure to DES can cause a variety of dysplasias. In the offspring of female mice exposed to DES during pregnancy, histological changes are observed in the vaginal and cervical epithelium, the endometrium, the ovary, the testis and the epididymis. Prenatal exposure of rats to DES led to decreased litter size and to urethrovaginal cloaca, penile and testicular hypoplasia, and cryptorchidism. Vaginal ridging, vaginal adenosis, testicular hypoplasia and cryptorchidism have been observed in rhesus monkeys following prenatal exposure. There is sufficient evidence that diethylstilboestrol is carcinogenic in experimental animals, after either prenatal or postnatal exposure. Mice show a similar type of carcinogenicity to that observed in humans, target organs being vagina, cervix, uterus, ovary, mammary gland and testis. In rats, prenatal exposure to DES produces mostly mammary and pituitary tumours, but also some tumours of the vagina. Hamsters develop tumours of vagina, cervix, endometrium, epididymis, testis, liver and kidney. DES induces ovarian papillary carcinomas in dogs, and malignant uterine mesotheliomas in squirrel monkeys. Some experimental evidence points to the possibility of a transgenerational carcinogenic effect, since prenatal treatment of mice with DES is followed by an increased incidence of uterine and ovarian carcinomas in the second-generation descendants. Experimental results could have been used to predict the adverse effects of DES observed in humans in the early 1970s: DES had been reported to be carcinogenic in mice in the 1930s, while experiments in the 1960s had provided evidence that exposure during pregnancy could result in an increased cancer risk in the progeny.

Diethylstilboestrol: I, Pharmacology, Toxicology and carcinogenicity in humans.

Diethylstilboestrol is still used as an adjunct palliative treatment in certain patients with breast and prostate cancer. Its pharmacological, toxicological and carcinogenic properties are reviewed. In addition to the usual untoward effects following subacute or chronic administration of oestrogens, treatment with diethylstilboestrol has been associated with serious cardiovascular sequelae. Most characteristic are, however, the carcinogenic properties of this drug. Many epidemiological data provide evidence that prenatal exposure to diethylstilboestrol is causally associated with vaginal and cervical clear-cell adenocarcinomas, a very rare type of cancer in the unexposed female population. The intrauterine exposure of males leads to an increased risk of testicular cancer, although the data are less conclusive in this respect. There is some evidence that administration of diethylstilboestrol in large doses to adult women during pregnancy increases the risk of subsequent breast cancer and it probably increases the incidence of endometrial carcinoma, as has been shown with other similar oestrogens given chronically for menopausal symptoms.

Cancer risks related to electricity production.

The International Agency for Research on Cancer has previously evaluated the cancer risks associated with fossil fuel-based industrial processes such as coal gastification and coke production, substances and mixtures such as coal tars, coal tar pitch and mineral oils, and a number of substances emitted from fossil-fuelled plants such as benzo[a]pyrene and other polycyclic aromatic hydrocarbons, arsenic, beryllium, cadmium, chromium, nickel, lead and formaldehyde. Based on these evaluations and other evidence from the literature, the carcinogenic risks to the general population and occupational groups from the fossil fuel cycle, the nuclear fuel cycle and renewable cycles are reviewed. Cancer risks from waste disposal, accidents and misuses, and electricity distribution are also considered. No cycle appears to be totally free from cancer risk, but the quantification of the effects of such exposures (in particular of those involving potential exposure to large amounts of carcinogens, such as coal, oil and nuclear) requires the application of methods which are subject to considerable margins of error. Uncertainties due to inadequate data and unconfirmed assumptions are discussed. Cancer risks related to the operation of renewable energy sources are negligible, although there may be some risks from construction of such installations. The elements of knowledge at our disposal do not encourage any attempt toward a quantitative comparative risk assessment. However, even in the absence of an accurate quantification of risk, qualitative indication of carcinogenic hazards should lead to preventive measures.

Inequalities in cancer risks.

Inequalities in health reflect social inequalities in society. The incapacity of our society to eliminate poverty is indeed one of the most blatant examples of failure in prevention. Every individual's health history is characterized by life-long influences and superimposed short-term factors, but health biographies of the rich and the poor show divergences that are the result of the accumulation and interaction of a series of events that may be quantitatively and qualitatively different. Schematically this could, for example, mean that certain individuals, or certain segments of the populations, are exposed more frequently and to more hazardous agents than others and/or less frequently to protective agents. Sanitary conditions are worse, mortality higher, survival rates of cancer patients lower, and life expectancy shorter in developing countries than in industrialized countries. The projection of the total number of cancer cases in the next decades indicates a general increase, proportionally greater in developing than in industrialized countries. Semin Oncol 28:207-209.

Toward the development of an equitable cancer prevention.

The most reasonable and socially acceptable development of cancer prevention should be the blending of the population approach, that is the shifting of the distribution of risk factors across an entire population in a favourable direction, with the high risk approach aimed at the identification, surveillance and possibly early interventions on individuals with particularly high values of predisposition to cancer. Interventions aimed at reducing or eliminating genetically determined weaknesses with regard to interactions with the environment, will not make, therefore, in any way obsolete or redundant, interventions aimed at eliminating or reducing exposure to environmental carcinogens.

Combined effects of fast-neutron irradiation and subcutaneously applied carbon tetrachloride or chloroform in C57Bl6 mice.

Male and female C57Bl6 mice received a single whole-body dose of irradiation with 170 rad or 330 rad of fast neutrons. Nine weeks later they were given a single subcutaneous injection of carbon tetrachloride or chloroform. Chloroform did not influence the occurrence of tumours, but carbon tetrachloride markedly increased the incidence of radiation-induced liver carcinomas.

Persistence of carcinogenic effect in intact progeny of mice treated transplacentally with 7,12-dimethylbenz[a]anthracene.

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.

Cell proliferation and carcinogenesis: a brief history and current view based on an IARC workshop report. International Agency for Research on Cancer.

The International Agency for Research on Cancer recently convened a Working Group of Experts (June 11-18, 1991) to discuss the use of information on carcinogenesis mechanisms in carcinogenic risk identification. The role of cell proliferation in carcinogenesis was among the items discussed in detail. It was recognized that cell proliferation is an important mechanistic aspect for both genotoxic and nongenotoxic carcinogens. It may act at each stage of the carcinogenesis process, altering the size of the pool of cells at risk for a next event. Cell proliferation was considered to be important, especially as a) an integral part of the process of converting DNA adducts to mutation, b) an enhancing factor for the mutation frequency by inducing errors in replication, and c) an important factor in determining dose-response relationships for some carcinogens. It was also recognized that not all agents that induce cell proliferation are necessarily involved in carcinogenesis; for example, a) not all skin hyperplasia-inducing compounds are skin tumor promoters, b) agents that induce "regenerative" cell proliferation appear to have different effects on tumor induction from agents that have a direct mitogenic effect, and c) the carcinogenic activity of many nonmutagenic agents depends on the continuous administration of the agent. In addition, tissues with a high rate of cell proliferation do not have a higher risk of developing cancer. Thus, no simple relationship exists between cell proliferation and carcinogenesis.