Salud y riesgo laboral:

citostáticos
CASO INTEGRADOR FINAL

Ivana Masci
01
Caso de
exposición
laboral
Información del caso
Salud y riesgo laboral: citostáticos
Utilizados como tratamiento farmacológico de
enfermedades neoplásicas (quimioterapia)

METABOLISMO DIVISIÓN
CELULAR

CITOTOXICIDA MUTAGENICIDAD
D
CARCINOGÉNESIS TERATOGÉNESIS

Reconstitución y formulación en farmacia hospitalaria

Manipulación bajo condiciones asépticas en cabinas de bioseguridad

En caso de inadecuada manipulación o funcionamiento de la cabina de bioseguridad
Exposición dérmica/mucosas: contacto con el compuesto
Exposición inhalatoria: formación de vapores
Penetración parenteral: pinchazos o cortes

Un caso de exposición
Enfermeras de una clínica en la Ciudad de Neuquén pertenecientes al
área de manipulación de citostáticos expresan que presentan síntomas
tales como prurito e irritación en piel y mucosas.

Se comprueba el mal funcionamiento de la cabina, no se puede estimar

el tiempo transcurrido desde el desperfecto
02
Aspectos a
contemplar
Abordaje de la evaluación de riesgo mediante la
conformación de un equipo multidisciplinario
Abordaje de la evaluación
Farmacéuticos Médicos Bioquímicos

Conocimiento de los Evaluación de la

protocolos de manipulación
historia clínica de cada Evaluación de
afectado marcadores de
exposición en
Farmacocinética y sangre/orina/pelo
farmacodinamia de los
citostáticos empleados
• Moléculas diana Evaluación de signos y
• Metabolismo síntomas clínicos
• Concentración Evaluación de
• Excreción (t1/2 y vía) marcadores de efecto
en sangre/orina/pelo/
Sugerencia de estudios mucosas
por imágenes y
Manipulación de solventes determinaciones en
sangre/orina
 03
Evaluación del
riesgo laboral
Establecimiento de una hoja de ruta para el estudio
 Estudios por Análisis de los
Reclutamiento de Evaluación imagen, resultados,
trabajadores Historia clínica y clínica determinaciones conclusiones y
afectados y de encuesta y obtención bioquímicas y tratamientos
un grupo control de muestras ensayos de para afecciones
genotoxicidad relacionadas
Reclutamiento de participantes

Grupo
Grupo expuesto control
Aquellxs trabajadorxs que Trabajadorxs del área y el hospital que
utilicen dicha cabina para no trabajen en la cabina disfuncional,
manipulación de fármacos, ni con rayos X, tratamiento de
ya sea que trabajen con quimioterápicos (ej administrativos)
citostáticos o no
Recopilación de datos
Registro de encuesta
*edad
*sexo
*embarazo en curso
*exposición laboral: fecha de comienzo, tipo, frecuencia, utilización de protecciones adecuadas y
seguimiento correcto de los protocolos
*enfermedades preexistentes o alteraciones en estudios sin llegar a enfermedad
*tratamiento crónico con algún fármaco o estudios que involucren rayos X con frecuencia
*hábitos higiénico-dietéticos (si fuma y frecuencia, si consume alcohol y frecuencia, fuente del agua
de beber)
*aparición de síntomas, tiempo desde que comenzaron, nivel de intensidad de los mismos

Evaluación de historia clínica

Muestras a obtener

Orina o pelo Hisopado

Sangre periférica nasal
Venopunción con EDTA Recolección de orina Realizado mediante hisopado
como anticoagulante de 24 hs o pelo estéril de las fosas nasales
Estudios a realizar
Evaluación de Evaluación del
la exposición efecto
Evaluación clínica de signos y
síntomas relacionados Estudios por imagen

Evaluación básica en sangre

Determinación de el/los Ensayos de MN en células
compuestos o sus metabolitos nasales, ICH y CPC y cometa en
en sangre periférica, orina o PBMCs
pelo
04
Análisis de
efecto
genotóxico
Test de MN, ICH con CPC y
ensayo cometa
 Ensayo de micronúcleo (citoma)
Análisis estadístico
% células MN
ANOVA entre grupos
Hisopado nasal Exclusión de individuos
(cepillo citológico estéril)
Observación al
microscopio
Siembra sobre Criterios de inclusión de
células, MNs y otras
portaobjetos alteraciones nucleares

Mínimo 1000 cel

Fijación Coloración
(metanol absoluto:ácido Hoestch/Feulgen/ Images of the different cell types`stained using Feulgen and Light Green scored in the BMCyt assay
acético glacial (3:1) Pap viewed by transmitted light or under fluorescence with a far red filter; (a) basal cell; (b) differentiated
fresco) cell; (c) early differentiated cell with micronucleus (arrow); (d) late differentiated cell with
micronucleus (arrow); (e) differentiated cell with nuclear bud (arrow); (f) binucleated cell; (g)
condensed chromatin cell; (h) karyorrhectic cell; (i) pyknotic cell; (j) Karyolytic cell. Upper panels
light microscopy, lower panels fluorescence microscopy. All images were taken at 1,000 magnification
Obtenido de Thomas et al 20091
Ensayo de ICHs y CPC Adaptado de Tumini et al 2021 2

Sangre periférica Coloración

Giemsa 3%
anticoagulada con EDTA

Cultivo en medio RPMI con SFB y fitohemaglutinina

Observación al
C+: mutágeno (mitomicina C) microscopio
ICH en M2
CPC
Evaluación de la cinética de proliferación celular (CPC)
𝑀 1+2 ∗ 𝑀 2+3 ∗ 𝑀 3
Índice de replicación (IR) = 100 Análisis estadístico
ANOVA entre grupos
Evaluación de la tasa de intercambio de cromátides hermanas (ICH) Exclusión de individuos

Promedio de ICH/célula (50 células en M2 por individuo)3

Ensayo cometa Acompañar con evaluación
de citotoxicidad

Agarosa 0.7%

20 min TA 1000
Sangre periférica g;

anticoagulada con EDTA

(criopreservación de hasta 3
meses)4
-Ajustar concentración
10 min -Incubación x 30 min
Lisis buffer (2.5 M NaCl, 100 mM Na2- -Buffer como control
EDTA, 10 mM Tris, 1% surcosinato de sodio
y 1% Triton X-100, pH 10)

30 min
0.83 V/cm

SYBR green
40 min
3 x 5 min
0.3 M NaOH, 1 mM
Tris
EDTA, pH > 13

Adaptado de Peter Møller et al (5)

05
Integración de
resultados
Análisis por individuo y
comparación entre grupos
Evaluación del riesgo
Encuesta
Evaluación clínica
Estudios por imagen Riesgo individual
Determinaciones bioquímicas
Ensayos de genotoxicidad

Comparación de resultados del

Riesgo ocupacional
grupo expuesto con grupo control

Hubo daño vinculado a la ruptura de la cabina?

Hubo individuos afectados?

Definir un tratamiento si fuese necesario y un protocolo de seguimiento

Referencias
1. Thomas, Philip et al. “Buccal micronucleus cytome assay.” Nature protocols vol. 4,6 (2009): 825-37.
doi:10.1038/nprot.2009.53
2. Tumini, Emanuela et al. “The Sister-Chromatid Exchange Assay in Human Cells”. In: Aguilera, A., Carreira, A. (eds)
Homologous Recombination. Methods in Molecular Biology, vol 2153. (2021). Humana, New York, NY.
https://doi.org/10.1007/978-1-0716-0644-5_26
3. Siddique, Yasir Hasan, and Mohammad Afzal. “Induction of chromosomal aberrations and sister chromatid exchanges by
chlormadinone acetate in human lymphocytes: a possible role of reactive oxygen species.” Indian journal of experimental
biology vol. 42,11 (2004): 1078-83.
4. Ladeira, Carina et al. “The comet assay for human biomonitoring: Effect of cryopreservation on DNA damage in different
blood cell preparations.” Mutation research. Genetic toxicology and environmental mutagenesis vol. 843 (2019): 11-17.
doi:10.1016/j.mrgentox.2019.02.002
5. Møller, Peter et al. “Minimum Information for Reporting on the Comet Assay (MIRCA): recommendations for describing
comet assay procedures and results.” Nature protocols vol. 15,12 (2020): 3817-3826. doi:10.1038/s41596-020-0398-1
Referencias
1. Thomas, Philip et al. “Buccal micronucleus cytome assay.” Nature protocols vol. 4,6 (2009): 825-37.
doi:10.1038/nprot.2009.53
2. Tumini, Emanuela et al. “The Sister-Chromatid Exchange Assay in Human Cells”. In: Aguilera, A., Carreira, A. (eds)
Homologous Recombination. Methods in Molecular Biology, vol 2153. (2021). Humana, New York, NY.
https://doi.org/10.1007/978-1-0716-0644-5_26
3. Siddique, Yasir Hasan, and Mohammad Afzal. “Induction of chromosomal aberrations and sister chromatid exchanges by
chlormadinone acetate in human lymphocytes: a possible role of reactive oxygen species.” Indian journal of experimental
biology vol. 42,11 (2004): 1078-83.
4. Ladeira, Carina et al. “The comet assay for human biomonitoring: Effect of cryopreservation on DNA damage in different
blood cell preparations.” Mutation research. Genetic toxicology and environmental mutagenesis vol. 843 (2019): 11-17.
doi:10.1016/j.mrgentox.2019.02.002
5. Møller, Peter et al. “Minimum Information for Reporting on the Comet Assay (MIRCA): recommendations for describing
comet assay procedures and results.” Nature protocols vol. 15,12 (2020): 3817-3826. doi:10.1038/s41596-020-0398-1
 0 1
Conformación del grupo
interdisciplinario
-Establecimiento del grupo
relacionado a la salud que
abordará la evaluación de
riesgo laboral desde diversos
aspectos
-Recopilación de
información relevante al
caso
-Determinación del grupo de
estudios y determinaciones a
realizar a los involucrados y
muestras a obtener
-Conformación de la
encuesta previa a los
estudios
Reclutamiento
-Contacto con el grupo de
personas afectadas
-Reclutamiento de personas
no afectadas por el infortuito
como grupo control
2 3
Evaluación clínica y
obtención de muestras
-Obtención de datos de cada
individuo de ambos grupos
mediante la encuesta
-Análisis de historia clínica
-Evaluación de signos y
síntomas
-Obtención de muestras de
hisopado nasal (para test
MN) y de sangre periférica
(para determinaciones
bioquímicas y tests de ICH,
IM, CPC, cometa)
Evaluación de
efecto
-Realización de
determinaciones en sangre
-Realización de estudios por
imagen en individuos del
grupo expuesto
-Realización de ensayos
para determinar inducción
de genotoxicidad (MN en
células nasales e ICH, IM,
CPC, cometa en LSP).
Análisis estadísticos de los
resultados.
4
Integración y
conclusiones
-Evaluación del resultado de
los análisis en sangre, por
imágenes y del studio de la
genotoxicidad
-Análisis por grupo y por
individuo
-Conclusiones sobre la
exposición y sus efectos si la
hubo
-Determinación de un
tratamiento de ser necesario
Educational Icons Medical Icons
Organelles and their functions

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Important functions
Cellular Processes
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Mercury is the closest Venus has a beautiful name Despite being red, Mars is
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Mercury is the closest Saturn is a gas giant and Jupiter is the biggest
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Mercury is the closest planet to the Sun and the smallest one in the Solar System.
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Earth is the only planet known Despite being red, Mars is Neptune is very far away from
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Saturn is a gas giant and has Mercury is the closest planet Jupiter is the biggest planet of
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Earth is the third planet from the Sun and the
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Mercury is the closest planet
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Venus has a beautiful name Earth is the third planet from
and is the second planet the Sun and the only one
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Despite being red, Mars is Jupiter is a gas giant and the
actually a cold place. It’s biggest planet in the Solar
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Mercury is very small Jupiter is a big planet

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Venus is a hot place
Cell Saturn has rings
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