Original Article

Occupational Health Status of

Workers Exposed to Female Hormones in
a Pharmaceutical Plant
T.V. RANGA RAO*, T. GURUSWAMY**, B.H. KHAWAS***

ABSTRACT
A large number of highly hazardous substances are handled in the pharmaceutical industry. One of the fundamental
features of the control of hazard arising from therapeutic materials is to identify the foreseeable effects of the agents
under conditions of use through a health surveillance system. A workplace can only be safe when both those who are
responsible for it and those who work in it fully understand both the risks involved and the systematic approach to
controlling them within acceptable limits.
An occupational health study was conducted in a pharmaceutical industry engaged in the manufacture of
contraceptive pills with a view to evaluate the health status of workers exposed to female hormones. The sample
included 11 workers from the steroidal section, 16 from the non-steroidal area and 11 control subjects. The findings
revealed that all the workers exposed to the hormones showed various manifestations attributable to the toxic effects
of exposure to high levels of airborne sex steroids in the work atmosphere as well as suppression of endogenous
hormones. The levels of norgestrel and ethinyl oestradiol and the dust containing the steroids in the work
environment were far exceeded the prescribed dose for contraception warranting urgent interventional strategies to
safeguard the health of the workforce.

1. INTRODUCTION A multidisciplinary occupational health study was

As a large number of highly hazardous substances
are handled in the pharmaceutical industry, it is
necessary to emphasize in outline the particular
problems which, may arise in the handling of
therapeutic materials and to indicate how these
problems may be controlled. One of the fundamental
features of hazard control is the need to identify the
foreseeable effects of the therapeutic agent under
conditions of use, to set up a health surveillance
system, which is capable of identifying these effects
should they occur and an information system which
allows the frequency and severity of any such effects
to be recorded and subsequently analysed as the
definitive way of confirming the adequacy of the
control strategy especially in the absence of a reliable
base for environmental standards.
* Director (Medical), Central Labour Institute, Mumbai-400 022.
** Formerly DD (Med.) &
*** DD (IH), Regional Labour Institute, Chennai-600 113.
conducted in a pharmaceutical industry engaged in
the manufacture of contraceptive pills. The study
findings are given in the present paper.
2. OBJECTIVES OF THE STUDY:
1. To assess the health status of workers exposed to
the steroids viz. Ethinyl estradiol and norgestrel.
2. To evaluate the working environment by determin-
ing the concentration of steroids i.e. Norgestrel
and Ethinyl Estradiol handled by the workers in the
making of contraceptive pills and to suggest
control measures whenever necessary.
3. GENERAL OBSERVATIONS
3.1 There were 27 employees in all including 2
officers in the process areas (11 in the steroidal
section, 14 in the non-steroidal area and 2 officers).
11 Male workers were employed in the steroidal area
for 3 months. After receiving health related complaints

17 INDIAN JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE VOL. 7, NO. 2, MAY-AUGUST 2003
from the workers, they were removed from the job
and 6 female workers were employed in their place
for the last one year. All the workers were in the age
group of 20 to 30 years.
Manufacturing Method:
The process of manufacture of the contraceptive pills
involved the following operations.
PREPARATION OF STEROIDS SOLUTION
MIXING / GRANULATION
DRYING
BLENDING
TABLETING
SIEVING
COATING
PACKING
The formulation was set for the manufacture of
21,00,000 tablets (one lakh cycles) in each batch
requiring mainly 640 gm of norgestrel USP and
64 gms of ethinyl estradiol IP.
3.2 Personal Protective Equipments Provided
It was observed that the workers were provided with
the following personal protective equipments:
(1) Cotton cap
(2) Full cotton face mask with opening for eyes,
covering head and face up to neck
(3) Apron and trouser made of cotton
(4) Gloves made of latex
(5) Cotton mask covering nose and mouth
(6) Half mask with dust filter.
4. TOXICITY OF CHEMICALS
4.1.1 Adverse Effects of Oestrogen in Women:
Prolonged oestrogen therapy has caused malignant
endometrial changes in predisposed persons.
18 OCCUPATIONAL HEALTH STATUS OF WORKERS EXPOSED TO FEMALE HORMONES IN A PHARMACEUTICAL PLANT
Women treated with oestrogen may complain of
menstrual disorders, nausea, headaches, etc. Similar
effects were observed during occupational exposure
to natural or synthetic oestrogens and oral
contraceptives. Menstrual disorders were frequent.
Metrorrhogia was observed in women who started to
work. Metrorrhagia occurred in women workers with
endometrial hyperplasia. Manifestations like metror-
rhagia, nausea and headache usually disappear after
discontinuance of exposure.
For contraception purpose a dose of 0.03 mg. ethinyl
oestradiol per day (24 hours) is recommended. With
this dose some women may show side effects like
nausea, headache etc.
4.1.2 Adverse Effects of Oestrogen in Men
Anorexia, nausea, vomiting, oedema, a feminisation
syndrome characterised by gynaecomastia (uni or
bilateral) increased pigmentation of the areola,
tenderness of the nipples with or without secretion,
loss of libido with difficulty in erection, with or
without involution of the secondary sex organs and
sterility (by inhibition of spermatogenesis), may
occur. Since it is a female hormone, no does for
men is prescribed.
4.2 Norgestrel:
4.2.1 Adverse Effects in Women:
Norgestrel is a progestin, a derivative of
progesterone. Excess of progesterone may be
responsible for weight gain, acne, mastalgia and
breast enlargement and recurrent monilial vaginitis.
Toxicity may also include headache, nausea,
chloasma, break through bleeding, weight gain, loss
of libido, cholestatic liver damage, sterility may also
occur. The normal dose recommended 0.3 mg
norgestrel per day (24 hours).
4.2.2 Adverse Effects in men:
Progestagens in excess, in men, besides the general
symptoms described in women, may inhibit
spermatogenesis.
4.3 Route of Entry:
Airborne particles of sex hormones may be absorbed
through the skin, ingested or inhaled. Enteric
absorption results in quick in activation of sex
hormones in liver. Sex hormones may accumulate
and reach relatively high level even if their absorption
is intermittent. Consequently, repeated absorption of
small amounts may be detrimental to health.
5. MATERIAL & METHODS
TABLE - I : DISTRIBUTION OF WORKERS ACCORDING
5.1 Medical Monitoring: TO AGE GROUP

All the 11 individuals working in the steroidal area; 14 GROUP <20 yrs. 21-25 26-30 31-35 36-40 Total
workers from the non-steroidal area who were M F M F M F M F M F M F
withdrawn from the steroidal area following the STEROIDAL – 1 – 4 1 1 2 1 – 1 3 8
development of health related problems; and 2
NON-STEROIDAL – – – – 2 – 12 – 2 – 16 –
officers who visit the section frequently were included
CONTROL – – – – 4 – 7 – – – 11 –
for the study. 11 workers from other areas were
included as the control group. The workers were TOTAL 01 04 08 22 03 38
interviewed with the help of a Questionnaire, about
their past occupational history, details of present TABLE - II : DISTRIBUTION OF WORKERS ACCORDING
TO LENGTH OF SERVICE
employment, personal history, the types of personal
protective equipment they were using etc. A detailed GROUP 00-02 03-06 07-12 13-24 Total Grand
history of their present complaints was recorded with Sex Months Months Months Months Total
particular emphasis to their menstrual history and STEROIDAL M 3 – – – 3 11
sexual problems. A thorough clinical examination was F 1 2 5 – 8
conducted on the workers with particular attention to
NON-STEROIDAL M – – 5 11 16 16
their endocrine problems and cardiovascular system.
F – – – – –
Routine urine examination for Albumen and sugar
was done using the Uristix strips. (Control group workers had length of service from 8-9 years)

ECG was taken for all the 38 workers examined by

using a computerised ECG machine. The workers
were subjected to volumetric pulmonary function
tests using a calibrated computerised Spirometer
(Medspiror) and measurements of FVC (Forced Vital
Capacity) and FEV1 (Forced Expiratory Volume in
one second) were made. The PFT results were
analysed as per the spirometric guidelines for
assessment of respiratory impairment.
steroidal exposure for a period ranging from 15 days
to 5 months (Following the development of some
steroid attributed health problems they were
withdrawn from the steroidal area and were engaged
in the non-steroidal area). The control group of
workers were taken from other Plant areas having no
potential of exposure to steroids and had length of
service varying from 8 to 9 years.

Blood samples were taken, from all the three groups
and the levels of FSH, LH, Progesterone, Oestradiol
and Testosterone were estimated by Radio Immuno
Assay.
5.2 Industrial Hygiene Monitoring:
Dust samples were collected using personal sampler.
A millipore filter paper type AA having pore size 0.8
micron and diameter 37 mm was used. The suction
rate was maintained at 1 lpm. Dust samples were
collected at different locations and near machineries.
The collected dust samples were analysed spectro-
photometrically using UV/VIS spectrophotometer.
Concentration of dust was determined gravimetrically.
6. RESULTS AND DISCUSSION
Table - I & II give the distribution of the workers as per
age groups and length of exposure. The workers had
minimum period of exposure of 15 days to the
steroids and to a maximum of one year duration. 13
out of 16 workers of non-steroidal group also had
The clinical findings of the workers examined were
given in Table-III. During our study in the steroidal
area 8 women and 3 men were examined. The clinical
findings and the symptoms developed in the past,
due to steroidal exposure were also elicited from the
workers of non-steroidal area. Eventhough in most of
the workers in the non-steroidal area, the symptoms
and signs were cleared, still some individuals had the
evidence of Gynaecomastia, pigmentation of areola
etc. All the 8 female employees of the steroidal area
complained of menstrual disorders. It can be seen
from Table-III, in the non-steroidal group, 12 out of 16
workers (75%), when they were working in the
steroidal area, had loss of libido; 7 (43.45%) workers
had mastalgia and 5 (31.25%) workers had loss of
appetite. In the steroidal group, 7 (63.63%) workers
had increased appetite, 4 workers (36.36%) with
increased body weight and 4 workers (36.36%) had
abdominal discomfort
Table-IV, V & VI show the level of the hormones viz.
Follicular Stimulating Hormone (FSH), Leutinising
Hormone (LH), Progesterone, Oestradiol and

19 INDIAN JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE VOL. 7, NO. 2, MAY-AUGUST 2003
 TABLE - III : CLINICAL FINDINGS OF WORKERS EXAMINED

GROUP STEROIDAL NON-STEROIDAL CONTROL

TOTAL
SEX M F M F M F
NO. OF WORKERS EXAMINED 3 8 16 – 11 – 38
SIGNS & SYMPTOMS NUMBER OF WORKERS AFFECTED
1. Headache 6 (54.54) – – 6 (15.79)
2. Giddiness 1 (9.09) 2 (12.5) 1 (9.09) 4 (10.53)
3. Nausea 6 (54.54) 1 (6.25) – 7 (18.42)
4. Vomiting 1 (9.09) – – 1 (2.63)
5. Loss of Appetite 3 (27.27) 5 (31.25) – 8 (21.05)
6. Increased Appetite 7 (63.63) 2 (12.5) – 9 (23.68)
7. Increased Body Weight 4 (36.36) 2 (12.5) – 6 (15.79)
8. Abdominal Discomfort 4 (36.36) 2 (12.5) – 6 (15.79)
9. Gynaecomastia – 3 (18.75) – 3 (7.89)
10. Mastalgia – 7 (43.75) – 7 (18.42)
11. Loss of Libido 3 (27.27) 12 (75.0) – 15 (39.47)
12. Pigmentation of Areola – 1 (6.25) – 1 (2.63)
13. Nipple Discharge – 2 (12.5) – 2 (5.26)
14. Menstrual Problems :
(1) Delayed Periods 8 (100%) – – 8 (100%)
(2) Menorrhagia 3 (37.5) – – 3 (37.5)
Parenthesis indicated percentage

TABLE - IV : BLOOD LEVELS OF HORMONES IN THE STEROIDAL (EXPOSED) GROUP

HORMONE 1 2 3 4 5 6 7 8 9 10 11 Normal Values

FSHMIU/ml. 24 ND 1.4 ND ND ND ND ND ND ND Male 1.1 – 13.5
Female Foll 3.3 – 8.8
Mid-Cycle 5.4 – 20.0
Luteal 1.6 – 8.7
LH MIU/ml. 10.5 ND ND ND ND ND ND ND ND ND Male 0.4 – 5.7
Female Foll 0.6 – 6.2
Mid-Cycle 12.0 – 51.0
Luteal ND – 6.0
PROGESTERONE Ng/ml. ND ND 0.44 ND ND ND 0.12 0.18 ND 0.19 Male ND – 0.6
Female Foll 0.1 – 1.5
Luteal 2.5 – 28
Mid ” 3.8 – 28
Oral Cont. 0.1 – 0.3
OESTRADIOL Pg/ml. 34.0 38.0 26.0 ND ND 42.0 ND ND 100.0 11.0 Male ND – 44
Female Foll –12 10 – 50
– 4 60 – 200
Mid-Cycle – 1 120 – 375
Luteal + 2 50 – 155
+ 6 60 – 260
+12 15 – 115
TESTOSTERONE Ng/dl 21.0 16.0 14.0 ND 3.0 32.0 16.0 6.0 6.8 24.0 Male 270 – 1070
Female 6.0 – 86

20 OCCUPATIONAL HEALTH STATUS OF WORKERS EXPOSED TO FEMALE HORMONES IN A PHARMACEUTICAL PLANT

 TABLE - V : BLOOD LEVELS OF HORMONES IN THE NON-STEROIDAL GROUP

Normal
HORMONE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Values
(Male)
FSH MIU/ml. 8.0 2.5 7.5 2.1 3.2 9.0 2.4 3.6 5.6 4.1 11.0 ND 2.7 3.6 4.8 6.0 1.1 – 13.5
LH MIU/ml. 1.7 6.2 3.0 6.8 2.9 8.5 ND 1.0 1.4 1.2 4.8 ND 1.9 1.7 1.7 1.6 0.4 – 5.7
PROGESTERONE 0.24 0.17 0.14 0.20 0.75 0.10 ND 0.23 0.46 0.56 0.56 ND 0.62 0.90 0.6 0.21 ND – 0.6
Ng/ml.
OESTRADIOL 41.0 32.0 32.0 28.0 34.0 10.0 36.0 21.0 36.0 58.0 56.0 ND 48.0 50.0 19.0 ND ND – 44
Pg/ml.
TESTOSTERONE 460 440 480 750 580 440 290 400 580 435 520 30.0 420 415 420 600 270 – 1070
Ng/dl

TABLE - VI : BLOOD LEVELS OF HORMONES IN THE CONTROL GROUP

HORMONE 1 2 3 4 5 6 7 8 9 10 11 Normal Values

(Male)
FSH MIU/ml. 3.0 2.2 5.0 2.0 4.2 2.4 5.8 4.1 2.8 4.2 2.3 1.1 – 13.5
LH MIU/ml. 1.0 1.7 3.0 1.5 2.8 2.5 3.6 2.0 6.2 2.4 1.0 0.4 – 5.7
PROGESTERONE Ng/ml. 0.54 0.48 0.54 0.40 0.56 ND ND 0.11 ND ND 0.66 ND – 0.6
OESTRADIOL Pg/ml. 36.0 66.0 36.0 30.0 72.0 30.0 40.0 75.0 17.0 44.0 52.0 ND – 44
TESTOSTERONE Ng/dl 360 440 400 340 420 500 540 290 380 520 480 270 – 1070

Testosterone. It can be seen that the levels of all the
hormones in the steroidal group were suppressed
when compared to the other two groups. The
increase in the level of FSH (24 MIU/m) in one female
worker, could be due to her exposure to small doses
of steroids especially ethinyl oestradiol because of
her supervisory work in the production areas.
Table-VIII shows the concentration of Norgestrel and
Ethinyl estradiol in air at various locations/operations.
The average concentration of Norgestrel and Ethinyl
estradiol in tableting section was found to be 2.75
TABLE - VIII : CONCENTRATION OF CONTAMINANTS
AT VARIOUS LOCATIONS/OPERATIONS

TABLE - VII : CONCENTRATION OF STEROID BEARING Sl. Location/Operation Average Conc. (mg/m3)
DUST AT DIFFERENT LOCATIONS No. Norgestrel Ethinyl
Estradiol
LOCATIONS Dust Conc. Dust Conc. Dust Conc. 1. Tableting Section 2.75 3.1
(mg/m3) (mg/m3) (mg/m3)
2. Tablet Sieving Operation 1.74 4.58
Max. Min. Average
3. Sieving & Mixing Room 2.5 1.67
SIEVING ROOM 44.67 37.33 41.0
Atmosphere
TABLETING ROOM 44.0 39.33 41.67
4. Near Mixing Machine 4.92 Sample Destroyed

5. Drying Room 1.35 1.67

Table-VII shows the average concentration of
Norgestrel and Ethinyl Estradiol bearing dust in air at
various locations. Results show that the average
concentration of dust in sieving room air was found to
be 41.00 mg/m3 while in tableting room the average
dust concentration was 41.67 mg/m3. The TLV for
steroid bearing dust is not available. It is reported in
literature that an industrial hygiene guideline of
0.05 mg airborne oestrogen dust per cubic metre
of air for an 8 hours work day (TWA) was adopted at
one manufacturing company. The values obtained
indicate that the concentration of steroid bearing dust
was considerably high at both the places.
6. Weighing Room 8.9 6.25
mg/m3 and 3.1 mg/m3 respectively. The average
concentration of Norgestrel and Ethinyl estradiol near
the sieving operation was found to be 1.74 mg/m3
and 4.58 mg/m3 respectively, while in sieving room
atmosphere the concentration of Norgestrel and
Ethinyl estradiol was found to be 2.5 mg/m3 and 1.67
mg/m3. It is also to be noted that the concentration of
norgestrel near mixing machine which is situated in
the room where sieving operation was carried on was
4.92 mg/m3. The concentration of Norgestrel near

21 INDIAN JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE VOL. 7, NO. 2, MAY-AUGUST 2003
sieving machine was found to be 1.74 mg/m3 while in
sieving and mixing room atmosphere it was found to
be 2.5 mg/m3.
The concentration of Norgestrel and Ethynyl Estradiol
in drying room air was found to be 1.35 mg/m3 and
1.67 mg/m3 respectively which may be due to
evaporation of active ingredients during drying
process. The concentration of Norgestrel and Ethinyl
Estradiol in the weighing room air at the time of
preparation of steroid solution was found to be
8.9 mg/m3 and 6.25 mg/m3 respectively.
7. CONCLUSIONS
1. All the workers exposed to the sex steroids,
showed the various steroid induced
manifestations attributable to exposure to high
levels of airborne steroids in the working
atmosphere as well as suppression of
endogenous hormones in the workers exposed to
norgestrel and ethinyl oestradiol.
2. The levels of norgestrel and ethinyl oestradiol
and the dust contraining the above steroids were
far higher than the prescribed dose for the
contraception i.e. Norgestrel with a minimum
airborne level of 1.35 mg/m3 to a maximum level
of 8.9 mg/m3 and the ethinyl oestradiol with a
minimum level of 1.67 mg/m3 to a maximum level
of 6.25 mg/m3. The normal dose prescribed for
contraception is 0.3 mg. norgestrel and 0.03 mg.
of ethinyl oestradiol per day (for women only).
8. RECOMMENDATIONS
1. The steroids should be mixed in a closed
container with mechanised agitator inside a
fume cupboard.
2. To avoid the vapours getting into the work
environment while mixing is carried out, the
solution should be added through the closed
vessel through a stop cock arrangement.
3. The outlet of the tableting machine should be
enclosed with dust extraction system.
4. Workers should be trained and encouraged in
the use of personal protective equipments at all
times.
5. It was recommended to provide a space suit
with supplied air hose pipe connection to
workers to avoid exposure to steroidal dust.
6. The workers employed in steroidal area should
be medically examined regularly, at periodical
intervals by an occupational health specialist.
REFERENCES
1. The United States Pharmacopeia, 22nd Revision, 1989.
2. Pharamacopeia of India, Vol. I, 3rd Ed. 1985.
3. N. Irving Sax, Dangerous Properties of Industrial Materials Sixth Ed.
1984.
4. Harrison’s Principles of Internal Medicine, 10th Ed.
5. Guidelines for the Control of Occupational Exposure to Therapeutic
Substances : The Association of British Pharmaceutical Industry,
London (1985).

Obituary
DR. J.C. PATEL
India lost one of the most brilliant physicians Dr. Jamnadas C. Patel on 11th May 2003.
Despite being born in a family of modest means, with determination, hard work and passion for learning
medicine, he went to England and acquired MRCP as well as Ph.D. in physiology. His life in medical
profession was filled with obstacles and rewards. He carried out many pioneering activities in the practice
and field of medicine in India. He gave long and meritorious service to KEM Hospital, Bombay Hospital
and Singhania Hospital in Bombay and also worked with large reputed corporations like Glaxo, Burmah
Shell and Hindustan Petrolium.
He was a man of courage and compassion; He was a good teacher, excellent clinician, and constructive
critic. He skillfully blended in his personality so many other qualities.
One of the first occupational health physicians of the country, he was elected President of IAOH in the
year 1952 and served the organisation as treasurer from 1954 to 1960.
He will remain immortal in the memory of all who knew him during his life.

22 OCCUPATIONAL HEALTH STATUS OF WORKERS EXPOSED TO FEMALE HORMONES IN A PHARMACEUTICAL PLANT